Much has been made about J. L. W. Thudichum’s colorful, and one could say clairvoyant, naming of sphingosine “in commemoration of the many enigmas which it presented to the inquirer” in his 1884 treatise The Chemistry of the Brain (1) because many of the riddles of sphingolipids (as the broader field was later named) (2) remained unanswered for the following century. This changed radically over the past several decades as researchers explored, and ultimately established, what seemed at the time to be radical concepts: that sphingolipids are not just structural elements of cells but also participate in intra- and extracellular signaling; that not only the complex glycan headgroups, but also the lipid backbones, are highly specified metabolically and have selective biochemical functions; and that even the longest known function of these lipids, as structural components of the “fluid mosaic” of cell membrane lipids, is not so simple, and often involves the dynamic clustering of sphingolipids in nontraditional microdomains referred to as rafts. We still know only a fraction of their secrets, but this enlightenment has defined models for thinking about these compounds that remove them from their enigmatic “black box.”

Now, a major challenge is to keep up with the rapid growth in knowledge about the sphingolipidome, that is, the ensemble of all sphingolipids. (3) A major goal of the review is to help the reader more easily grasp the metabolic interrelationships that account for the tens of thousands of molecular subspecies (and perhaps more) that appear in nature, with a focus on mammals. The magnitude of this subject precludes the inclusion of all of the enzymes and metabolites, and the author apologizes for the omission of many interesting topics. To put this information in context, there is a brief background discussion of their structures and functions, which have been dealt with also in a recent Chemical Reviews article (4) on the chemicophysical features of sphingolipids and raft formation, and by excellent reviews on sphingolipid signaling (5, 6) and the biological functions of complex glycosphingolipids. (7-10)

An Overview of Sphingolipid Structure and Function

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Sphingolipids share the common structural feature that all are comprised of backbones called “long-chain-” or “sphingoid” bases, which are represented by sphingosine, (2S,3R,4E)-2-aminooctadec-4-ene-1,3-diol (also referred to as (E)-sphing-4-enine) 1, the major sphingoid base found in mammals. Free sphingoid bases (i.e., underivatized) are typically present in very small amounts because most are amide-linked with a long- or very-long-chain fatty acid to form ceramides 2 that can be further derivatized by addition of a headgroup (at C1 in 2) to form more complex sphingolipids such as sphingomyelin (SM), glucosylceramide (GlcCer), galactosylceramides (GalCer) and more complex glycosphingolipids with a few to dozens of sugar residues. (3) There are also small amounts of “lyso-”sphingolipids (i.e., sphingoid bases plus a headgroup but lacking the N-acyl-substituent, such as sphingosine 1-phosphate, sphingosine 1-phosphocholine, and lyso-glycosphingolipids), N-methyl-derivatives, and covalent adducts with proteins.

Backbone and Headgroup Nomenclature

Because organisms usually have more than one type of sphingoid base (e.g., not just sphingosine 1, but also sphingoid bases with more or fewer hydroxyls, somewhat shorter or longer alkyl chains, and other structural variations), (11) a convenient short-hand nomenclature to distinguish them by these features is to give the number of hydroxyl groups (m for one, mono-, d for the two, di-, and t for three, tri-) followed by the chain length and number of double bonds (with their position, if necessary). Therefore, sphingosine 1 is usually abbreviated d18:1, with the double bond assumed to be at position 4, or specified by a prefix (4E-d18:1) or superscripted suffix (d18:1^Δ4t). The addition of an amide-linked fatty acid to form a ceramide can be designated by a semicolon or slash followed by the carbon chain length and number of double bonds for the fatty acid. Using this nomenclature, the Cer 2 (N-palmitoylsphingosine) would be abbreviated d18:1;C16:0 (or d18:1/C16:0, or 4E-d18:1;C16:0, etc.). This can be added to the name of the sphingolipid headgroup subcategory (as shown in Figure 1 for ganglioside GM1a) to provide explicit information about the molecule that is being described.

Figure 1. Basic structures of mammalian sphingolipids. The upper left panel summarizes the categories of complex sphingolipids, and the upper right panel displays the root structures of the glycosphingolipid families using the glycan symbols defined by the key in the lower panel (the letter and number within the symbols convey the nature of the glycosidic linkage between that carbohydrate and the species to its right, for example: “β4” represents a β1–4 linkage). The abbreviations are: Glc, glucose; GlcNAc, N-acetylglucosamine; Gal, galactose; GalNAc, N-acetylgalactosamine; Neu5Ac, N-acetylneuraminic acid; Fuc, fucose. The lower panel displays the structure of ganglioside GM1a using both ChemDraw and glycan symbols, the Roman numbering system for the positions of the glucans (i.e., beginning with the first carbohydrate attached to ceramide), and a comparison with two other gangliosides (GM1b and fucosyl-GM1a) using the glycan symbol system.

The major headgroup types and some aspects of their nomenclature are shown in Figure 1. They can be categorized as having substituents that are nonpolar (H- and O-acyl) versus polar (phospho- and glyco-) or polar with an ionic group (phosphate, carboxyl for N-acetylneuraminic acid and glucuronic acid, or sulfate). The phosphosphingolipids of mammals are ceramide 1-phosphate (Cer1P), sphingomyelins (SM) and ceramide phosphoethanolamines (CerPE) (plus the “lyso” forms of these, that is, with the sphingoid base but not amide linked fatty acid). The glycosphingolipids are divided into multiple subcategories: first by whether they have glucose (GlcCer) or galactose (GalCer) as the carbohydrate attached in β-linkage to Cer, then by the nature of the additional substituents (for example, sulfated glycosphingolipids are referred to as sulfatides). GlcCer is followed by addition of Gal to form Galβ1–4Glcβ1Cer (lactosylceramide, LacCer), which is at a branchpoint for formation of the so-called root structure families (globo-, isoglobo-, lacto-, neolacto-, and ganglio-) shown in Figure 1. Likewise, the order and position of addition of other substituents, in particular the addition of N-acetylneuraminic acid (Neu5Ac,which is also called sialic acid) defines branching families of glycosphingolipids (in this case, gangliosides), with ganglioside GM1a shown as an example in Figure 1 as both a chemdraw structural diagram and commonly used symbols (see key in Figure 1). (12) It is worth mentioning that there are structural differences in the repertoire of carbohydrates that are used among even fairly closely related mammals, for example, the sialic acid of human gangliosides is primarily comprised of N-acetylneuraminic acid (Neu5Ac) as shown for GM1a in Figure 1 whereas other mammals have both Neu5Ac and N-glycolylneuraminic acid (abbreviated Neu5Gc), which cannot be made by humans. (13)

Many of the glycosphingolipids are comprised of the same units attached in different combinations and arrangements, as exemplified in Figure 1 by the root structure families globo- versus isoglobo- and lacto- versus neolacto- (as well as by the two gangliosides GM1a and GM1b) and, thus, glycosphingolipid biosynthesis has been described as nature’s version of combinatorial chemistry. (14)

There are several nomenclature systems for glycosphingolipids, and many compounds are still referred to by their historically assigned names (such as gangliosides GM1a and GM1b shown in Figure 1). Using IUPAC-IUB guidelines for systematic naming of glycosphingolipids, (15, 16) these gangliosides would be described as Neu5Acα2–3(Galβ1–3GalNAcβ1–4)Galβ1–4Glcβ1Cer (d18:1/C18:0) for GM1a, and Neu5Acα2–3Galβ1–3GalNacβ1–4Galβ1–4Glcβ1Cer (with the same Cer backbone specification, if it applied) for GM1b. These compounds could also be named starting with the Ganglio (Gg) root structure that they both share (see insert in the upper right of Figure 1) with designation of the location of the Neu5NAc along the chain using Roman numerals (this numbering system is shown for GM1a) and Arabic superscripts to designate the hydroxyl- to which the Neu5NAc is linked. By this system, GM1a is described as II³-α-Neu5NAc-Gg₄Cer (which would be read “II³-α-N-acetylneuraminosyl-gangliotetraosylCer”) and GM1b is IV³-α-Neu5NAc-Gg₄Cer (IV³-α-N-acetylneuraminosyl-gangliotetraosylCer). When there are additional modifications, such as 9-O-acetylation of sialic acid (13, 17) or formation of an intramolecular lactone, (18) these are added to the name. Some other glycans that are still referred to by historic names are the Lewis blood group antigens (Figure 2). (19, 20)

Figure 2. Representative structures of Lewis epitopes. The key for the glycan symbols is the same as for Figure 1.

The biological rationale behind this structural complexity is no mystery when one considers the sophistication of the functions of sphingolipids, as represented schematically in Figure 3. Complex sphingolipids (shown here as SM, in black, and gangliosides GM3 and GM1a, using the headgroup key from Figure 1) help form lipid bilayers with unique surface characteristics (charge, polarity and morphology) and fluidity, which contribute to the clustering of sphingolipids and cholesterol (and some proteins) in rafts. (4, 21) Also depicted are interactions between surface glycosphingolipids and proteins on the same cell, the extracellular matrix, neighboring cells, and other entities (such as bacterial toxins and viruses), which have been referred to as the “glycosynapse.” (22) Sphingolipids additionally contribute to membrane dynamics (23) and cell regulation through metabolic interconversions (shown for SM and Cer, which can occur via sphingomyelinases and SM synthase) (24) and membrane trafficking, (21, 25) and this can lead to production of additional bioactive metabolites (Cer1P, sphingosine and S1P) (26) that act in situ, inside, or outside of the cell (as shown for S1P and an S1P receptor). (6) Although these functions (both of the complex sphingolipids and the “signaling” lipid moieties) are shown at the plasma membrane, where they certainly can occur, (27) the lipid backbones from de novo sphingolipid biosynthesis also contribute to signaling (28) (sometimes with deleterious consequences), (29) and sphingolipids have functions in previously unexpected organelles such as the nucleus, (30) and in some cases using enzymes classically thought to be active only for “housekeeping” turnover of sphingolipids, such as acid sphingomyelinase. (31) It will be a challenge to figure out which specific sphingolipid molecules (and combinations of molecules) are present and interacting with which specific targets to achieve the sphingolipid-regulated steps in a biological process.

Figure 3. Schematic representation of sphingolipid functions. This diagram depicts a hypothetical plasma membrane with representative categories of sphingolipids with the black headgroup representing sphingomyelin, the colored headgroups the glycosphingolipids as in Figure 1, and the lipid backbones with the sphingoid base in blue and the amide-linked fatty acid in gray; phosphoglycerolipids and cholesterol are depicted in gray. The diagram illustrates the clustering of a portion of the sphingolipids (and cholesterol) in membrane “rafts,” the binding of ganglioside GM3 (left) and GM1 (right) to proteins, and the metabolic interconversions of some of the sphingolipids (shown in the box, in the order ceramide 1-phosphate, ceramide, sphingosine, and sphingosine 1-phosphate, S1P), which alters both the biophysical properties of the membrane and generates signaling molecules, such as S1P, which is involved in both intracellular signaling and extracellular signaling (represented by the green arrow).

Variation in the Lipid Moieties

Some of the breakthroughs in understanding the functions of sphingolipids, especially with respect to cell signaling, have come from having the capacity to measure more than one bioactive subspecies so the correct signaling pathways can be sorted out, (32) especially when the metabolites have opposite effects, such as ceramide versus S1P. (33) In recent years, the analytical technology of choice has been mass spectrometry; (34, 35) however, even when the analysis of the lipid moieties of sphingolipids was quite laborious (for example, using chemical degradation to determine sphingoid base composition), (36, 37) the few biological samples that were examined in depth gave an astonishing result, that is, that a given class of sphingolipid is comprised of dozens of different backbones, not just the handful that are usually discussed. (38) Indeed, a recent analysis of human plasma SM using a mass spectrometry protocol that is able to distinguish the isobaric and isomeric subspecies (using a technique we refer to as “ion trap facilitated fragmentation”) (39) identified ∼100 different lipid subspecies, (40) and other types of mass spectrometry have uncovered an equivalent level of structural diversity with mammalian samples. (41)

Sphingoid Base Diversity

Sphingoid bases vary in type (such as sphingosines versus sphinganines) (Figure 1) and chain length. Two of the most common chain length variants of sphingosine (d18:1) 1 are d16:1, which has been found, for examples, in plasma sphingolipids (40, 42) and bovine milk, (43, 44) and d20:1 (eicosasphingosine), which is present in substantial amounts in brain gangliosides, especially with advanced age. (45) Other locations include human stomach and intestinal mucosa, (46) skin ceramides, (47) sulfatides, (48) and perhaps most puzzlingly, in host liver SM from rats bearing Morris hepatoma 7777. (49) Mammalian sphingoid bases also include odd chain length variants (e.g., linear d17- and d19-, but odd carbon numbers are sometimes due to branched alkyl chains) and shorter chain-length subspecies (which are in trace amounts in mammals, but more common in other organisms, such as Drosophila (50)). (11) This variation has important implications for analysis of sphingolipids by mass spectrometry, which follows specific molecular ions and fragmentation products (often as precursor-product pairs) (40) so the bookkeeping of how much of a particular category of sphingolipid is present (for example, all the SM’s) will depend on successful inclusion of all of the subspecies in the analysis protocol (within the detection limits selected by the investigator).

Little is known about the biological significance of this seemingly subtle backbone chain-length variation, however, the alkyl-chain length mismatch has substantial biophysical consequences. (51) And if selective anatomical localization of d20:1 sphingosine is an expression of the adage that “form follows function,” it is noteworthy that gangliosides from sensory nerve contain larger proportions of d18:1 than motor nerve gangliosides (which have higher d20:1). (52) The very powerful technique of tissue-imaging mass spectrometry has established that d20:1 gangliosides are selectively localized along the entorhinal-hippocampus projections, especially in the molecular layer of the dentate gyrus, whereas those with the 18-carbon sphingoid base backbone are widely distributed throughout the frontal brain. (53)

Other types of structural variations that have been found in humans are shown in 3 to 7 (these also appear in other alkyl chain lengths). (11)

Sphinganine (also referred to as dihydrosphingosine) 3 is an intermediate of sphingoid base biosynthesis and is found in most complex sphingolipids in at least small amounts; 4-hydroxysphinganine 4, which is often referred to as phytosphingosine, is commonly found in sphingolipids from epithelial tissues (54) and skin (which also has another trihydroxy-sphingoid base with the extra hydroxylation at postion 6 rather than 4, 5). (47, 55-58) In addition to these, the diene 6 has been noted in plasma (40) and brain, (59, 60) and other mammalian sources. (61) Sphingadienes with double bonds at other positions (62-64) (and trienes) (65) are found in plants, and have been reported in SM from human breast milk. (66)

Sphingoid bases 7 and 8 have been found in mammals only recently, (67, 68) and are very intriguing because they lack the 1-hydroxyl-group that is found on all of the other sphingoid bases, which means they (or the N-acyl-“1-deoxydihydroceramide” derivatives) can not be metabolized to more complex sphingolipids by headgroup addition. They are mainly present as the N-acylated (1-deoxydihydroceramide) metabolites, (67) which will be extremely hydrophobic. It is not clear how they are catabolized since degradation of the typical sphingoid bases proceeds via the 1-phosphates. (69)

Some of the structural variety found with other organisms (11, 36, 37) is illustrated by examples 9–12. The branched triene 9 has been identified in squid nerve sphingomyelin, (70) aplidiasphingosine 10 has been isolated from the marine tunicate Aplidium sp. (71, 72) and noted to have antimicrobial and antitumorial activity, (71, 73) and obscuraminol 11 was isolated from a chloroform extract of Pseudodistoma obscurum (74) that was cytotoxic for various tumor cell lines (but the isolated compound was only mildly cytotoxic). Calyxinin 12 is a member of a fascinating series of compounds that resemble “two-headed” sphingoid bases, that is, two sphingoid bases connected tail-to-tail (note that the lower portion of calyxinin resembles sphinganine the upper portion a 1-deoxysphinganine at the other end with threo- stereochemistry). (75) These and other extraordinary sphingoid bases (11) warrant attention because they might be useful tools for studies of sphingolipid metabolism or functions (as will be discussed below for two stellar examples, fumonisin B₁13 and myriocin 14). Furthermore, some might appear in humans if consumed in the diet (or, perhaps, produced de novo but previously overlooked). Indeed, both apply to 1-deoxysphinganine 7, which was first named spisulosine upon its isolation from Spisula polynyma, (76) a clam that is consumed by humans as sushi, chowder and “clam strips” (appearing in recipes as the Arctic surf clam or Stimpson’s surf clam). It was later found to be made by mammals. (67, 68)

The fungal secondary metabolites fumonisin B₁13 and myriocin 14 are the two most widely studied extraordinary sphingoid bases. Soon after the structure of fumonisin B₁ was elucidated, (77) its similarity to sphinganine led to Ron Riley and my laboratories to explore if it might affect sphingolipid metabolism and the discovery that fumonisins are potent inhibitors of ceramide synthase. (78) Furthermore, this inhibition is thought to be a major contributor to the diseases caused by this family of mycotoxins, including a recent association with birth defects. (79) Fumonisin B₁ has been employed in hundreds of studies of sphingolipid metabolism, and is a useful tool if the investigator bears in mind that it also causes accumulation of sphingoid bases and often their 1-phosphates. (80) Likewise, myriocin (also called ISP-1) has been of tremendous value in sphingolipid research as a potent inhibitor of serine palmitoyltransferase, (81-83) and studies of immunosuppression by myriocin (81, 83, 84) led to the development of FTY720 (Fingolimod) 15, a compound that undergoes phosphorylation and disrupts lymphocyte trafficking by binding to S1P receptor(s). (85) FTY720 has shown promise in treatment of a number of diseases, including multiple sclerosis. (85, 86) Interestingly, cis-4-methylsphingosine 16 is another sphingoid base analog that is readily taken up by cells, undergoes phosphorylation, and affects S1P receptors; (87) it also inhibits de novo sphingolipid biosynthesis. (88)

Thus, many of these compounds might serve as pharmacophors for development of novel therapeutic agents. The sphingoid base safingol (l-threo-sphinganine) 17 was one of the first sphingoid base analogs to be tested as a potential anticancer agent because it inhibits protein kinase C and has a longer half-life than naturally occurring sphingoid bases (and is now of interest also because it inhibits sphingosine kinase and induces autophagy). (89, 90) Safingol has been evaluated in a phase I clinical trial alone and in combination with cisplatin and, in addition to defining the dosages that can be administered safely, the studies found that Safingol caused a dose-dependent reduction in S1P, as predicted. (91) A synthetic 1-deoxy-sphingoid base analog, Enigmol (92)18, has shown efficacy against using colon and prostate cancer in mouse models. And, phase I clinical trials have also been conducted with 1-deoxysphinganine 7 (under the name ES-285), (93, 94) which surfaced in a screen of lipid extracts from aquatic organisms for potential anticancer compounds. (95)

The mechanisms of action of sphingoid bases have been difficult to pin down because they affect many targets, which include receptors, protein kinases and ion transporters, (96-98) and because they are metabolized to and from other highly bioactive compounds (Cer, S1P, and others) (as depicted in Figure 3). Sphingolipids are also produced by yeast, and an understanding of signaling by free sphingoid bases is becoming clearer for that organism. (99)

N-Acyl-sphingoid Bases (Ceramides)

Acylation of the amino group of sphingoid bases with a fatty acid produces compounds broadly referred to as “ceramides” 2, although another current convention is to use this term specifically for N-acylsphingosines, and to apply other descriptors when a different sphingoid base is present, such as dihydroceramides for N-acylsphinganines and 4-hydroxyceramides or phytoceramides for N-acyl-4-hydroxysphinganines. The fatty acid chains are predominately 14 to 36 carbon atoms in length, and usually saturated, or with a single double bond or an α-hydroxyl group. Some of the most structurally complex ceramides are found in skin, which includes the presence of a very-long-chain fatty acid (C30 to 32) with an ω-hydroxyl group that is esterified to another fatty acid, (100-102) and in testis, which contains neutral glycosphingolipids with very-long-chain (C26 to C32) polyunsaturated (4 to 6 double bonds) fatty acids. (103, 104) Ceramides with very short fatty acids, as short as two carbons (acetyl-, C2-Cer), have also been found in mammals (105) and suggested to arise from transfer of the acetyl group from platelet-activating factor. (106)

Ceramide nomenclature follows the conventions already discussed. If the fatty acid is not stated explicitly (e.g., N-palmitoylsphingosine), the fatty acyl-chain length is usually presented as a prefix, such as C16-Cer for N-palmitoylsphingosine, or by the abbreviated nomenclature described in section 2.1.1. (d18:1/C16:0, 2).

Synthetic ceramide analogs have been prepared for a wide range of purposes, including the production of species that are more readily taken up by cells (e.g., C2-ceramides), (107) for exploration of structure–function relationships in cell signaling, (108) as inhibitors of enzymes of ceramide metabolism (109) (including an interesting case where 1-methylthiodihydroceramide 19 inhibits Cer biosynthesis by inducing sphingosine kinase), (110) and development of novel compounds that have shown activity as potential anticancer agents, such as l-threo-C6-pyridinium-ceramide-bromide 20 (which targets the nucleus and mitochondria), (111) the 4,6-diene-Cer 21 (112) (i.e., which contains an additional trans-double bond between carbons 6 and 7, like the 14-carbon sphingoid base from Drosophila that has been reported to prevent intestinal tumorigenesis (98)) and N-(4′,5′-dithiaheptanoyl)-D-erythro-Cer (113)22. Novel methods of delivery of ceramides (namely, C6-ceramide) have been developed by preparation of nanoliposomal particles to facilitate solubility (114) and are showing efficacy in cancer chemotherapy. (115, 116)

The biophysical properties of ceramides include many interesting features, (51) most notably that the alkyl chains are largely saturated and thus have high phase transition temperatures and give rise to rigid ceramide-enriched domains in membranes of otherwise more “fluid” components. (23) These properties are not generalizable to all “ceramides,” however, and raft stability is affected by the ceramide N-acyl chain, (117) among other factors. Ceramides also change membrane curvature, (118) transbilayer (flip-flop) movement of lipids (119) and other molecules, (120) appearing to form channels in mitochondrial outer membranes when present in sufficient concentrations. (120)

Cell signaling by ceramides has been elegantly reviewed many times (5, 31, 121-125) (just to list a few) and its roles in regulation of cell growth, senescence and death account for the aforementioned interest in ceramide analogs and modulators of ceramide metabolism as potential anticancer agents. (124, 126, 127) The regulation of autophagy by both ceramide (128, 129) and de novo synthesized dihydroceramide (97) is intriguing because this is different than for most of the other cellular processes regulated by ceramide (e.g., apoptosis), which require the 4,5-trans double bond. This raises the possibility that cells might use these relatively safe molecular subspecies for autophagy under conditions where comparable elevation of ceramides might be dangerous. This underscores how specific molecular subspecies are likely to be important for normal cell function, and the corollary that cells will have mechanisms to produce and localize the appropriate subspecies for the necessary structural and regulatory functions. In the words of Hannun and Obeid in a recent review: “First and foremost, the ‘Many Ceramides’ approach negates the current prevailing paradigm that ceramide can be understood in terms of regulation and function as a single entity... at the very least mechanistic studies on ceramide function and regulation should focus on specific pathways of formation.” (125) The mechanisms for formation of specific ceramide subspecies will be discussed in section .

Variation of the Complex Sphingolipid Headgroups

For the purpose of this review, complex sphingolipids will be defined as having both of the alkyl chains of the lipid moiety (i.e., “ceramide”) and a substituent at the hydroxyl at position 1. The major headgroup categories for mammalian sphingolipids (ceramides, sphingomyelins, glucosylceramides, galactosylceramides, etc.) are summarized in Figure 1, and this shows only a fraction of the glycan headgroups (Robert Yu has recently compiled structures for 174 neutral glycosphingolipids, 190 gangliosides and 24 sulfated glycosphingolipids); (19) the total estimate is closer to 600 if one adds likely biosynthetic intermediates that have not yet been characterized (for a depiction of these, see www.sphingomap.org). (3) The number expands considerably if one adds headgroups (and backbones) that are found in other organisms, such as plants, (130) fungi (131-133) and other organisms. (134) Even this summation is likely to underestimate the total as more sensitive analytical methods allow us to see minor subspecies.

Fortunately (for the analytical chemist), the number of species that are produced biologically will be much lower than the number that could be theoretically made from these glycans (if all combinations and positional isomers are considered) due to the relatively limited number of synthases for the complex sphingolipids and their substrate specificities. For an idea of how many species might theoretically exist, Roger Laine estimated that six different hexoses could be combined to form >10¹² different hexasaccharides, ∼10¹⁵ heptasaccharides, >10¹⁸ octasaccharides, and nearly Avogadro’s number for nonasaccharides. (135) Mind-boggling numbers, indeed! But, as one examines some of the largest mammalian glycosphingolipids, such as the placental tetrasialosylpoly-N-acetyllactosaminyl ganglioside 23 shown here, (136) it is striking that it is comprised of a few repeating units (for which these types of compounds have been named “polylactosaminoglycans”). (137)

Therefore, one can imagine that there might be a relatively simple biosynthetic pathway for such compounds with a few enzymes that act repetitively on the growing chains. This illustrates how cells might make many complex glycosphingolipids using a relatively small number of glycosyltransferases, and conversely, how the existence of a finite number of glycosyltransferases determines that cells will produce only a fraction of the theoretical number of combinations and permutations of the glycans.

Phosphosphingolipids

The simplest complex phosphosphingolipid is ceramide 1-phosphate, which has not yet been studied much for molecular subspecies but methods for its analysis have been developed. (39, 138) The N-acyl-chain length of Cer1P is influenced by its site of synthesis, with the Cer1P that is made de novo being enriched in C16-subspecies because it acts on Cer that have been delivered by the ceramide transport protein (CERT), (139) which is selective for long-chain versus very-long-chain Cer. The biological functions of Cer1P are still being discovered, but include phagocytosis, (140) stimulation of DNA synthesis, (141) inhibition of apoptosis, (142) activation of mTOR and RhoA, (143) and activation of phospholipase A2 (144) and production of eicosanoids (145) and lipid droplets. (146)

The most prevalent phosphosphingolipid in most mammalian tissues (and lipoproteins) is SM, and its chain length diversity has already been mentioned with respect to the ∼100 molecular subspecies in human plasma. (40) Besides its well-known membrane properties, (147, 148) it has been suggested that the N-acyl chain length affects endocytic trafficking of SM. (149) Bacteria produce a SM-binding protein (Lysenin) that is a pore-forming toxin (150) that has also been useful in studies of SM-mediated signal transduction. (151)

Mammals also produce small amounts of ceramide phosphoethanolamines, (152-154) although these are found in more substantial amounts in other organisms, such as chickens (in liver) (152) and Drosophila melanogaster. (155) Fungi, plants, and other organisms have inositol phosphorylceramides and other types of glycophosphosphingolipids, often with novel lipid backbones, (133, 156, 157) and they have been suggested to have functions in intracellular processes and cell-to-cell interactions, including between cells of different species in host–pathogen interactions. (158)

Glycosphingolipids

Mammalian glycosphingolipids begin with either glucose or galactose attached to the 1-hydroxyl of Cer via a β-glycosidic bond. In addition to being intermediates in the biosynthesis of more complex glycosphingolipids, these monohexosylceramides have also been suggested to have biochemical functions. GlcCer plays a critical role in skin (as a precursor that is hydrolyzed to skin ceramides to form the permeability barrier), (55) and is required for intracellular membrane transport, (159, 160) cell proliferation and survival, (161) multidrug resistance, (162, 163) and natural killer T cell functions. (164) In addition, the levels of GlcCer are altered by a wide spectrum of diseases, including cardiovascular disease, cancer, diabetes, and skin disorders. (161) Galactosylceramide (and its sulfated derivatives, termed sulfatides) are major components of myelin and have been reported to interact with each other by carbohydrate-carbohydrate interactions, perhaps on apposing surfaces of the multilayered myelin sheath. (165) Considerable attention has been given to α-GalCer, with an α-versus the β-glycosidic linkage, which was originally uncovered in studies using extracts from sponges and is now synthetically produced as KRN7000, because it is a potent activator of iNKT cells and promotes immunotolerance. (166) It is also of interest that the cytokine profile induced by GalCer has been found to be affected by the nature of the lipid backbone. (167, 168)

GalCer are sulfated to produce the acidic glycosphingolipids referred to as “sulfatides” (GlcCer is also sulfated to 3′-sulfo-Glcβ1Cer, SM4s-Glc in some tissues). (4) 3-O-sulfogalactosylceramide (3′-sulfo-Galβ1Cer, also called cerebrosulfatide or GalCer-I³-sulfate) is a major component of the myelin sheath in the central and peripheral nervous system, kidney, gastrointestinal tract and endometrium. (169) Sulfatides are thought to be involved in neuronal cell differentiation, myelin formation and maintenance, (9) and it has been suggested that sulfatide interacts with GalCer in myelin through trans-carbohydrate–carbohydrate interactions. (165) Sulfatides additionally affect the behavior of macrophages, (170) participate in adhesion of leukocytes to selectins, and are thought to be involved in platelet aggregation via P-selectin (with inhibition of the P-selectin–sulfatide interaction leading to a reversal of platelet aggregation). (171) Other extracellular proteins that have been found to bind sulfatides include laminin and thrombospondin (172) and hepatocyte growth factor. (173) It should also be borne in mind, however, that some of the regulatory functions might be intracellular, because sulfatides bind to the N-terminal domain of sphingosine kinase 2. (174) Sulfatides are elevated in a wide range of cancers, including colorectal, (175) hepatocellular, (176) renal, (177) brain, (178) small-cell lung, (179) and ovarian (180) cancers, and are thought participate in metastasis. (175, 181)

The major disaccharide (Galβ1–4Glcβ1-ceramide), lactosylceramide (LacCer), is a critical intermediate in the biosynthesis of all of the root structure families of more complex sphingolipids (Figure 1). LacCer has been proposed to function in cell signaling pathway(s) that affect cell proliferation, adhesion, migration, angiogenesis, phagocytosis and inflammation. (182-185) In human neutrophils, the Src family kinase Lyn appears to be coupled with LacCer-enriched domains in the plasma membrane so that ligand (i.e., microorganism) binding to LacCer activates Lyn, triggering neutrophil functions, such as superoxide generation and cell migration. (186) Interestingly, the LacCer must have a very-long-chain fatty acid (C24:1 or C24:0) in the ceramide moiety, perhaps because that is necessary for proper membrane interdigitation and organization. (186, 187) It is also possible that LacCer participates in glycan–glycan interactions with other glycosphingolipids, such as GM3. (188)

One of the simplest glycosphingolipids (with three carbohydrates) is ganglioside GM3, Neu5Acα2–3Galβ1–4Glcβ1Cer. A function for GM3 in the regulation of cell proliferation was uncovered several decades ago by Hakomori and his colleages, who found that GM3 inhibits the stimulation of growth by epithelial growth factor (EGF) via inhibition of the activation of the EGF receptor tyrosine kinase. (189, 190) Subsequent studies revealed that the interaction at the surface appears to be via glycan–glycan binding involving multivalent GlcNAc termini on the EGF receptor, (191) and that the intracellular consequences are prevention of the autophosphorylation of the intracellular kinase domain and the allosteric structural transition to a signaling dimer. (192) This (and a similar finding that GM1 inhibits growth stimulation by platelet derived growth factor, PDGF) (193) defined the paradigm for ganglioside action illustrated in Figure 2, that is, that they not only help define the properties of the surface of the plasma membrane but also interact with surface proteins to modulate their function. Gangliosides are expressed on essentially all vertebrate cells, and typically with tissue-selective, and often developmentally related, profiles, that is, with varying types of headgroups and lipid backbones, (7) and in addition to modulating the way cells respond to a wide range of growth factors (EGF, PDGF, VEGF, and others), they interact with glycan-binding proteins on apposing cells via receptors called Siglecs that function in cell–cell recognition. (7, 194) Gangliosides have been found to regulate natural killer cell cytotoxicity via Siglec-7, myelin-axon interactions via Siglec-4 (also referred to as myelin-associated glycoprotein, MAG), and inflammation via E-selectin. (7) Some sialic acid-containing glycosphingolipids are very large, such as the tri- and tetra-sialosylpoly-N-acetyllactosaminyl gangliosides of human placenta that have >20 residues, (136) and might function to create a surface or barrier with particular biophysical properties.

The globo (Gb) and isoglobo (iGb) series trihexosylceramides are abbreviated Gb3 and iGb3, respectively. As shown in Figure 1, they differ only with respect to the terminal glycosidic linkage, which is α1–4 in Gb3 and α1–3 for iGb3. Gb3 has received much attention because it accumulates in Fabry’s disease due to defective α-galactosidase A (195) and because it is bound by (and receptor for) Shiga toxin, (196) verotoxins and the HIV adhesin gp120. (10) Interestingly, the lipid backbones Gb3 also have a substantial effect on the way these proteins behave in cells, and might be important to the eventual pathogenic outcome. (10) Gb3 is elevated in numerous cancers (colorectal adenoma, Burkitt’s lymphoma, breast cancer and testicular carcinoma), (197) and a correlation between Gb3 and metastasis has been seen for colorectal cancer. (198) The relationships are being explored as a way for cancer detection and targeting using Shiga toxin. (199, 200) The story for iGb3 is less clear because although it stimulates NKT cells and has been hypothesized to be a natural modulator of them, recent studies have found that the human iGb3 synthase gene contains several mutations that render its product nonfunctional (in constrast to rat, where iGb3 synthase is intact and iGb3 is found). (201) Therefore, iGb3 is unlikely to represent a primary natural ligand for NKT cells in humans and iGb3 itself would be expected to be recognized by the immune system as a foreign antigen, which might cause humans to reject transplanted tissues from animals that express this gene and iGb3, such as pigs. (201)

The first compound in the lacto-/neolacto- category, Lc3 (GlcNAcβ1–3Galβ1–4Glcβ1Cer), appears to be important for embryonic development and brain morphogenesis because knockout mice for Lc3 synthase gene display preimplantation lethality. (202) The animals that are successfully born have reduced survival and display pleiotropic phenotypic changes, including dwarfism, fur loss, and obesity. (203)

These examples illustrate how disruption of the production of one category of complex sphingolipids can impact survival and physiological functions. The reader is referred to the references already cited and others (204-207) for more information about additional glycosphingolipid structures and functions. Online sources that are also useful include: (i) the Consortium for Functional Glycomics (http://www.functionalglycomics.org/); (ii) the Complex Carbohydrate Research Center at the University of Georgia (http://www.ccrc.uga.edu/∼moremen/glycomics/); (iii) GlycoForum (http://www.glycoforum.gr.jp/); (iv) the KEGG ontology for glycosyltransferases (http://www.genome.jp/kegg/glycan/GT.html); and (v) LIPID MAPS (www.lipidmaps.org).

Other Types of Compounds

The term lysosphingolipid usually refers to a complex sphingolipid without the N-acyl-fatty acid, such as sphingosylphosphocholine (sphingoid base 1-phosphocholines) from SM, sphingosine-1-β-glucoside or -galactoside (“psychosines”), and other lyso-glycosphingolipids. Not much is known about the origins and functions of these compounds, although they have been found in blood and tissues in varying amounts and tend to be highly bioactive. (208, 209) For example, sphingosylphosphocholine display behaviors that might implicate it as an important lipid mediator in tissues such as heart, blood vessels, skin, brain, and immune system. (210) It has also been strongly implicated as a player in atopic dermatitis (211) via a SM deacylase that also acts on GlcCer. (212) The accumulation of psychosines was one of the hypotheses for the unusual cellular and biochemical characteristics of globoid cell leukodystrophy (Krabbe disease), as has been discussed. (213)

Trace amounts of N- and O-methyl-sphingoid bases are sometimes found in mammalian sphingolipids and are thought mostly to be artifacts of the extraction and handling. (214, 215) Nonetheless, a sphingosine N-methyltransferase activity has been found in mouse brain, (216) and when mice have been treated with safingol, the metabolites included the N-methyl-, N,N-dimethyl- and N,N,N-trimethyl-derivatives (and methylated sphingosine and sphinganine were detected); (217) therefore, there is an in vivo capacity to methylate sphingoid bases.

Sphingolipids have also been found as covalent adducts in the cornified cell envelope of the skin, (218-220) and yeast have been found to make glycosylphosphatidylinositol-anchored proteins with ceramide as the lipid moiety. (221)

Sphingolipid Metabolic Pathways

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The major focus of this discussion of the sphingolipid metabolic pathways will be to explain how the different subspecies are produced and, in some cases, how defects in these metabolic steps result in disease, rather than how the pathways are regulated, which would be a more monumental task. This begins with how the sphingoid bases arise since, by definition, all sphingolipids are comprised of that backbone. Most organisms derive a significant portion of their sphingoid bases from de novo biosynthesis because the first enzyme of the pathway (serine palmitoyltranserase) is essential for survival of cells in culture, from yeast (222) to mammals, (223) unless exogenous sphingoid bases are provided, and elimination of this enzyme is embryonic lethal for animals large (i.e., mammals) (224) and small (e.g., fruit flies). (225) This requirement appears to be due to the efficient degradation of sphingoid bases taken up by the intestine (via phosphorylation at the 1-hydroxyl then cleavage to a fatty aldehyde and ethanolamine phosphate), (226-229) which might exist to allow mammals to be selective in which species are in their repertoire, since a much wider variety of sphingoid base structural variants are found in other organisms (and, thus, in food). (11, 230) The fate of dietary sphingolipids warrants further investigation, nonetheless, when one considers that humans have been estimated to consume more than one hundred grams of sphingolipids per year. (230) Furthermore, dietary sphingolipids have been well established to be protective against cancers of the intestine (231-236) and other sites (237) in studies of experimental animals, and recent studies of sphingoid base analogs reveal that some structural variants are well absorbed, as exemplified by findings with Enigmol 18, (92) a synthetic 1-deoxy- analog similar to compounds found in some foods. (11)

Biosynthesis of the Lipid Moieties de Novo

Approximately one decade after elucidation of the definitive structure of sphingosine by Herb Carter and colleagues in 1947, (238) its biosynthesis in vitro was achieved by Brady and co-workers. (239, 240) Another decade later, Braun and Snell (241) and Stoffel et al. (242) demonstrated that the initial biochemical reaction is the formation of 3-ketosphinganine by condensation of serine and palmitoyl-CoA followed by rapid reduction of the intermediate ketone to produce sphinganine, if NADPH is also present; thereby establishing the first steps of sphingoid base biosynthesis de novo (Figure 4). In the early 1990s, the genes for the enzyme that catalyzes the initial reaction, serine palmitoyltransferase (SPT), were identified in yeast (LCB1 and LCB2) (243, 244) and soon afterward for mammals (SPTLC1, SPTLC2, and SPTLC3), (245-247) followed in relatively rapid succession by discovery of genes for most of the other enzymes of ceramide biosynthesis (as discussed below). Thus, the major steps for biosynthesis of the lipid moieties of sphingolipids are now fairly well mapped out biochemically and genetically, although additional features will undoubtedly surface over time, as for other pathways.

Figure 4. De novo sphingolipid biosynthesis through lactosylceramide and sulfatide. Starting at top left, serine and palmitoyl-CoA are condensed by serine palmitoyltransferase (SPT) to form 3-ketosphinganine that is reduced to sphinganine, which is N-acylated by ceramide synthases (CerS) with the shown fatty acyl-CoA preferences, or phosphorylated by sphingosine kinase (SphK). The N-acylsphinganines (dihydroceramides, DHCer) can be incorporated into more complex dihydro-sphingomyelins, SM, from sphingomyelin synthases, SMS; -ceramide 1-phosphates, CerP, from ceramide kinase, CERK; -glucosylceramides, GlcCer, from GlcCer synthase; and -galactosylceramides, GalCer, from GalCer synthase). DHCer is also oxidized to Cer by dihydroceramide desaturase (DES1 and DES2; DES2 is also capable of hydroxylating the 4-position to form 4-hydroxydihydroceramides, t18:0) and incorporated into more complex sphingolipids as shown. The diagram also displays the formation of lactosylceramide (LacCer) from GlcCer and sulfatides (ST) from GalCer, and the turnover of DHCer to sphinganine (and Cer to sphingosine), which can be recycled or phosphorylated and cleaved to fatty aldehydes and ethanolamine phosphate. Not shown is ceramide phosphoethanolamine, which is present in mammalian cells in nearly trace amounts. The key is shown at the bottom, and is the same as for Figure 1 except that heavy black boxes represent SM, thin black for Cer1P, and (DH)Cer are represented by the green octagon.

Formation of the Sphingoid Base Backbones

SPT is a pyridoxal 5′-phosphate (PLP)-dependent enzyme that catalyzes the condensation of serine and palmitoyl-CoA (and other amino acid and fatty acyl-CoA cosubstrates, as will be discussed later). It is a member of the PLP-dependent α-oxoamine synthase (POAS) subfamily and, like most POAS members, shares a conserved motif (T[FL][GTS]K[SAG][FLV]G on SPT2) that contains an active site Lys that is responsible for formation of a Schiff’s base with PLP. (248) For most organisms, (249) SPT is comprised of at least two separate polypeptides (and perhaps higher aggregates) (250) that are located in the membrane of the endoplasmic reticulum. There is also evidence for SPT being present in other regions of the cell, such as focal adhesions (251) and the nucleus (and, interestingly, appearing to shift to the nucleus in proliferating cells). (252) In the endoplasmic reticulum, the active site appears to be oriented toward the cytoplasm, (253, 254) as for the other enzymes of ceramide biosynthesis. (253) It is likely that SPT interacts with other regulatory proteins. Yeast SPT requires an additional 10-kDa peptide for optimum activity, (255) and although a mammalian homologue of Tsc3 was not found, (256) several categories of proteins have been suggested to play a regulatory role for mammalian SPT, including two small SPT subunits, ssSPTa, and ssSPTb, that appear to influence the fatty acyl-CoA selectivity, (257) ER proteins that might enhance Ser utilization (termed Serinc1 to 5), (258) and ORM1. (259, 260) Using tandem-affinity purification and mass spectrometry) to discover protein–protein interactions, a substantial number of proteins have been identified as potential LCB2-associated proteins in Saccharomyces cerevisiae. (261) These proteins are involved in various biological processes such as vesicle transport, nuclear import and export, among others. A genome-wide yeast two-hybrid analysis in Drosophila (262) has suggested that SPT2 may interact with 13 proteins, which include a proton transporter, organic cation transporter, hsc-70, and ribosomal proteins, among others.

Figure 5. Proposed reaction mechanism for serine palmitoyltransferase (modified from D. J. Campopiano and colleagues, (263-265) see text). Starting with the enzyme with pyridoxal 5′-phosphate (PLP) bound as a Schiff’s base with an active site Lys (upper left), Ser is bound to make the external aldimine 24 then palmitoyl-CoA is bound and the reaction proceeds as shown until 3-ketosphinganine 30 is released.

Elegant structural and spectroscopic studies have been conducted with SPT from the Gram-negative bacterium Sphingomonas paucimobilis, (263-265) which is a soluble homodimer with ∼30% amino acid sequence identity with mammalian SPT1 and SPT2, (266) and Sphingobacterium multivorum. (267, 268) These have supported the general mechanism shown in Figure 5. As for many PLP-dependent enzymes, (269) the amino acid substrate is covalently bound to PLP as a Schiff base 24 (which is often referred to as the “external aldimine” versus the “internal aldimine” that is produced by the enzyme-Lys-PLP Schiff base). Spectroscopic evidence has indicated that there is a structural rearrangement of this chromophoric species upon binding of the second substrate, a fatty acyl-CoA. The proposed steps for condensation of the substrates (Figure 5) are similar to what was deduced decades ago by isotope kinetics studies (270) and generally occurs with PAOS family enzymes: deprotonation at Cα of the external aldimine complex 25 to form a quinonoid intermediate 26 and a Claisen condensation with the acyl-CoA substrate and loss of free CoASH; this β-ketoacid intermediate 27 is doubly β,γ-unsaturated and undergoes decarboxylation to form another quinonoid intermediate 28 that rearranges to acquire a proton to form the product external aldimine 29 that is released from the enzyme as 3-ketosphinganine 30.

It was once presumed that SPT is specific for l-serine, however, recent studies of the effects of fumonisin B1 on animals and cells in culture (67) and of the disease human hereditary sensory neuropathy type 1 (HSN1), which is caused by mutations in SPT, (271-273) have found that wild type, and especially mutant, (68, 274-276) SPT is also able to utilize l-alanine and glycine to produce cytotoxic 1-deoxysphinganines and 1-(deoxymethyl)sphinganines, as shown in Figure 6. Like sphinganine, these “atypical” sphingoid bases are rapidly N-acylated, (67, 277) which might explain why their production even by wild type SPT had escaped previous notice. Studies of one of the disease-causing mutations (C133W in SPTLC1) (276) indicate that the wild-type and mutant enzymes are not altered in serine utilization and have similar apparent binding affinities for alanine, but the C133W mutation appears to enhance the condensation of alanine with the acyl-CoA substrate. It is very intriguing that SPT (even wild-type SPT) (67) is able to utilize this ensemble of metabolically interrelated substrates, Ser and Gly are interconverted via serine hydroxymethyltransferase, and Ser is catabolized to pyruvate (a precursor for Ala) via serine dehydratase, (278) at a crossroad of major metabolic pathways, which include glycolysis, amino acid metabolism, lipid metabolism and one-carbon metabolism (with implications for nucleotide biosynthesis) (Figure 6). Thus, many factors might affect their amounts and, indeed, elevated production of 1-deoxysphingolipids has recently been proposed to play a role in diabetes. (279) In another context, these compounds appear to have beneficial functions as an anti-cancer compound (280) that has been evaluated not only with cancer cells in culture (281) but also by phase I clinical trials. (94, 282) Surprisingly high dosages were tolerated in the trials, although the reported side effects included a case of peripheral motor and sensory neuropathy. (94)

Figure 6. Comparison of the structures of the “typical” and “atypical” sphingoid bases and the interrelationships between intermediary metabolism and the precursor substrates for them. The interconversion of Ser and Gly are catalyzed by serine hydroxymethyltransferase, and Ser is converted to pyruvate by serine dehydratase. Ser, Ala, and Gly are related to other metabolic pathways as illustrated, and produce the shown sphingoid bases when utilized by serine palmitoyltransferase.

SPT also binds d-serine as a competitive inhibitor with an IC₅₀ of ∼0.3 mM (which is similar to the K_m for l-serine), (256, 283) but does not appear to be utilized as a substrate. d-serine is found in plasma (284, 285) and urine, (286) and has been shown to be nephrotoxic, (287) so inhibition of SPT by d-serine might occur under some in vivo circumstances.

As implied by its name, SPT is usually most active with palmitoyl-CoA (C16:0-) as the cosubstrate, but it can accommodate fatty acyl-CoAs that are longer and shorter by one carbon fairly well, (248, 256) but these are usually much less prevalent than palmitoyl-CoA in mammalian cells. (288) These factors probably account for the high proportions of 18-carbon-chain-length sphingoid bases in most mammalian sphingolipids. It appears that another SPT isoform (SPTLC3) has a preference for myristoyl-CoA (C14) (289) and the amounts of C16-sphingoid bases are more substantial when this SPT isoform is expressed. (290) Such shorter chain length sphingoid bases are common in insects such as Drosophila, which contain C14- and 16-sphingoid bases and differ in regions of SPT that might account for this difference. (291, 292) C20-sphingoid bases are found in human gangliosides, (293) and it is not clear why or how they are elevated although the production of C20-sphingoid bases might be determined by expression of ssSPTb. (257) Interestingly, in yeast, C20-sphingoid bases are elevated under certain stages of growth and stress, and are thought to have roles in cell signaling. (99) Enhanced de novo biosynthesis of sphingolipids when cells are treated with palmitate (294) might link this pathway and the lipotoxicity of this fatty acid for many cell types, (295) and perhaps through elevated sphingosine 1-phosphate. (296)

SPT is potently and selectively inhibited by several naturally occurring compounds, (81, 297-299) such as myriocin (ISP-1) 14 (which has obvious structural similarity to active site intermediates) (Figure 4), sphingofungins, lipoxamycin (neoenactin M₁), and sulfamisterin, as well as by viridiofungins, which are also potent but additionally inhibit squalene synthase. (300) As would be predicted for an enzyme that utilizes PLP as a cofactor, SPT is inhibited by compounds such as β-chloro-l-alanine (301) and cycloserine, (265) and O-tert-butyl-l-serine methyl ester hydrochloride has also been reported to be inhibitory. (302) These inhibitors have been quite useful in studies of the roles of de novo synthesized sphingolipids in normal and abnormal cell functions, as has a mammalian cell line (CHO-LY-B cells) (303) that cannot make sphingoid bases due to loss of catalytic activity due to a G246R transformation in SPT1, (304) and knockout mice. (305)

After establishment of the chain length and subcategory of sphingoid base (i.e., traditional sphingoid base type versus 1-deoxy- or 1-(desoxymethyl)-sphingoid base), further modifications, such as introduction of the 4,5-trans double bond of sphingosine and the 4-hydroxylgroup of 4-hydroxysphinganine (phytosphingosine) generally take place after the 3-keto-sphingoid base has been reduced by an NADPH-dependent reductase (306) and N-acylated, as described in the following sections.

Ceramide Synthases

As shown in Figure 4, sphinganine is at the next key branchpoint in the pathway, where it is either acylated to different dihydroceramides by a family of Cer synthases (CerS) (307, 308) or phosphorylated to sphinganine 1-phosphate by sphingosine kinase(s). (309, 310)

The first genes coding for Cer synthases (CerS), Lag1p and Lac1p, were found in Saccharomyces cerevisiae, (311, 312) followed by identification of a lower molecular weight protein that is also required for activity. (313) Soon thereafter, mammalian homologues of Lag1p were characterized and the first cloned CerS (originally called lass1, and now referred to as CerS1) was found to be highly selective for stearoyl-CoA and to make C18-(DH)Cer. (314) This was followed by characterization of five additional CerS with distinct substrate selectivities (summarized in Figure 4) and other features, such as relative mRNA expression level and tissue distribution, that were consistent with the types of ceramides found in the respective source. (307, 308, 314-319)

CerS1 has been found to have an additional mode of regulation in that it is turned over rapidly under basal conditions, and even more rapidly under stress from agents such as UV light and chemotherapeutic drugs. (320) Turnover of CerS1 proceeds via ubiquitination and proteasomal processing, with translocation from the endoplasmic reticulum to the Golgi apparatus. (321) The subcellular localization of CerS1 might explain why administration of exogenous sphingosine to cells in culture disproportionately elevates C18-Cer. (309) Ogretmen and co-workers (322) have discovered that head and neck tumors have lower CerS1 and lower proportions of C18-Cer than neighboring normal tissue (consistent with the substrate specificity of CerS1 for C18-fatty acyl-CoA, as shown in Figure 4). In addition, decreased C18-Cer levels were significantly associated with the higher incidences of lymphovascular invasion, pathologic nodal metastasis, and the overall stage of the primary tumors. (323) These correlations were shown to have functional consequences by transfection of the CerS1 gene into head and neck tumor cells in culture, which restored the levels of C18-Cer and suppressed cell growth. (322) Therefore, CerS1 and C18-Cer appear to play important roles in the pathogenesis or progression of head and neck cancer. C18-Cer has been reported to result in repression of the hTERT promoter via deacetylation of Sp3 by histone deacetylase 1 (HDAC1) in A549 human lung adenocarcinoma cells. (324) Up-regulation of CerS1 has also been suggested to participate in the induction of apoptosis in chronic myeloid leukemia cells by dasatinib. (325) Studies of two mouse strains, flincher and toppler, with spontaneous recessive mutations that cause cerebellar ataxia and Purkinje cell degeneration have found that the mutations reside in the CerS1 gene, resulting in complete loss of CerS1 catalytic activity. (326) In addition to Purkinje cell death, there was also accumulation of lipofuscin, which is common with aging and in some neurodegenerative diseases, thus, might implicate CerS1/C18-Cer in these processes. (324)

CerS2 mRNA is found at the highest level of all CerS and has the broadest tissue distribution. It prefers the longer chain fatty acyl-CoAs, as shown in Figure 4, and there is a good correlation between CerS2 mRNA levels and the prevalence of those acyl chains in ceramide and sphingomyelin. Interestingly, CerS2 has an S1P receptor-like motif that raises the possibility that the activity of CerS2 might be regulated by S1P. (327) CerS2 is the only CerS for which there is currently a knockout mouse. (328-330) The mice were essentially devoid of very-long-chain (C22 and C24)-Cer and downstream sphingolipids, which is also consistent with the substrate specificity of CerS2 toward these chain length fatty acyl-CoAs (Figure 4). Apparently as compensation for the lower very-long-chain sphingolipids, C16-Cer-sphingolipids were elevated, and differences were observed in the biophysical properties of lipid extracts isolated from liver microsomes, with membranes from CerS2 null mice displaying higher membrane fluidity and differences in morphology. As part of the “sphingolipidomic” analysis of these mice by our lab, (329, 330) we discovered that sphinganine was elevated, by up to 50-fold, which was reminiscent to inhibition of ceramide synthase by fumonisins. (80) This was striking because, as occurs when mice are exposed to fumonisins, the livers of the CerS2-knockout mice developed severe hepatopathy from about 30 days of age, and displayed increased rates of hepatocyte apoptosis and proliferation progressing to hepatomegaly and noninvasive hepatocellular carcinoma later in life. (330) These data suggest that CerS2 is important for the synthesis of dihydroceramide and prevention of the accumulation of sphinganine. It also appears to be particularly important for synthesis of myelin sphingolipids (331) because the mice displayed encephalopathy, which may be largely because of reduced galactosylceramide levels. (332) CerS2 mRNA expression has been noted to be significantly elevated in breast cancer tissue compared to paired normal tissue. (333)

CerS3 is particularly important in epidermal keratinocytes and male germ cells, which produce large amounts of sphingolipids with very-long-chain- (C26–C36) Cer. (334) Its expression in keratinocytes increases upon differentiation, and it can produce 2-hydroxy-Cer, which are common in the epidermis. (335) Studies of mouse embryonic stem cells and embryoid bodies have found that the latter have higher CerS3 mRNA and higher proportions of C18-, C24- and C26-, and less C16-dihydroceramides. (336) Treatment of a mantle cell lymphoma cell line (Rec-1) with the endocannabinoid analogue R(+)-methanandamide has been reported to increase C16-, C18-, C24-, and C24:1-Cer and found transcriptional induction of CerS3. (337) All of these are consistent with the fatty acyl-CoA selectivity for CerS3 shown in Figure 4.

CerS4 has been studied less than the other CerS, perhaps in part because the Cer subspecies that it makes (C20 ± 2 carbons) (315) are not prevalent in most sphingolipids. It is expressed at highest levels in skin, leukocytes, heart, and liver. (327) Studies with a pancreatic beta-cell model, INS-1 beta-cells, found that supplementation of the medium with high glucose and palmitate increased CerS4. (338)

CerS5 and CerS6 are often considered in concert since both make C16-Cer, with CerS6 also utilizing myristoyl-CoA to make C14-Cer, as shown in Figure 4. CerS5 was the first mammalian CerS that was purified and proven to be a genuine synthase for ceramide. (317) Co-immunoprecipitation studies suggest that CerS2, 5, and 6 might exist as heterocomplexes in HeLa cells. (339) A number of factors induce CerS5 and CerS6, such as development, (340) ionizing radiation, (339) the cyclooxygenase-2 (COX-2) inhibitor celecoxib, (341) and the death receptor ligand TRAIL (tumor necrosis factor-related apoptosis-inducing ligand). (342)

Despite having differences in fatty acyl-CoA-specificity, the CerS have similar apparent Km toward the sphingoid base substrate sphinganine (ranging from 2 to 5 μM). (343) This implies that as sphinganine is made de novo, its partitioning into different categories of (dihydro)Cer will be governed by the relative levels of the CerS in its vicinity. This has fairly consistently been supported by the studies described above, where particular CerS were varied in amount in relationship to the other isozymes, and by a study by Obeid and co-workers (344) where individual CerS were suppressed in MCF-7 cells using small-interfering RNA (siRNA). (344) As was seen in the CerS2 knockdown mouse, (329, 330) elimination of one CerS often resulted in counter-regulation of one or more of the other CerS and corresponding shifts in the chain lengths of the cellular ceramides such that overall levels of complex sphingolipids were generally maintained despite reduction of a particular CerS (however, free sphinganine was not elevated in the siRNA studies). (344) It is not clear if the components of this pathway are present in the ER as discrete polypeptides that release their products into the ER membrane to diffuse to the next enzyme, or if there are macromolecular complexes that position the active sites so the product of one enzyme is released near the active site for the next enzyme. There is precedent for this latter scenario in recent findings with ELOVL1, a fatty acyl-CoA elongase that is essential for production of very long-chain fatty acids that are used by CerS2. (345) This might also account for the elevation of sphinganine in the CerS2 knockout mouse. (329, 330)

There are a large number of naturally occurring inhibitors of CerS, (11) with the best characterized (because of their public health relevance) being the fumonisins, a family of mycotoxins produced by Fusarium verticillioides (346) that cause a wide range of diseases of agriculture animals (equine leukoencephalomalacia and porcine pulmonary edema) and humans (cancer and birth defects). (79, 347) The structure of fumonisin B1 13 and the characteristics of the inhibition suggest that the aminopentol backbone competes for binding of the sphingoid base substrate, whereas the anionic tricarballylic acids may interfere with binding of the fatty acyl-CoA. (348) Inhibition of what appears to be all CerS (based on complete blockage of de novo sphingolipid biosynthesis) is accompanied by dramatic elevations in sphinganine and sphinganine 1-phosphate at early times, later elevation of sphingosine and S1P (from blockage of reutilization of the backbones of sphingolipids that are turning over), and depletion of complex sphingolipids --all of which are likely to contribute to fumonisin toxicity, carcinogenicity (348, 349) and teratogenicity. (79, 350) There is also an intriguing interplay between TNFα and fumonisins (351-353) which might be related to the ability of cytokines to affect sphingolipid biosynthesis and turnover. (354-356) Somewhat paradoxically, but of possible clinical importance, treatment with fumonisin B1 has been found to significantly reduce the systemic toxicity, weight loss, and mortality of zymosan-induced nonseptic shock in mice. (357)

Cer can also be made by reversal of acid ceramidase with a strict stereochemical requirement for d-erythro-sphingosine, (358, 359)d-erythro-sphinganine, and d-erythro-phytosphingosine but can occur with a wide spectrum of fatty acids, including both saturated and unsaturated fatty acids (358) and chain lengths varying from C8 to C22. (359) Detergents, pH, and various lipids, such as cardiolipin, phosphatidylcholine, and lysophosphatidylcholine can affect the hydrolysis reverse activity of ceramidases. (359) This appears to contribute little to Cer synthesis in vivo (as discussed above), however, recent findings with neutral ceramidase-deficient mice indicate that it might play a role in ceramide formation in mitochondria. (360)

N-acetyl-sphingosine (C2-Cer) and -sphinganine (C2-DHCer) have been reported to be made by a platelet-activating factor (PAF)-dependent transacetylase (361) that is widely distributed among tissues and appears to be more active with sphingosine than sphinganine. (106) This transacetylase is a multifunctional enzyme with three catalytic activities (lysophospholipid transacetylase, sphingosine transacetylase, and acetylhydrolase) and its regulation differs for macrophages compared to monocytes. (362) C2-DHCer has also been found in cells and animals treated with fumonisin B1 (as well as the untreated controls), (348) but it is not clear if this is produced by the PAF transacetylase or a more generic acetyltransferase used in detoxification of xenobiotics.

Desaturation and Hydroxylation of Dihydroceramide to Form Ceramides and 4-Hydroxyceramides (Phytoceramides)

Ong and Brady first suggested that incorporation of the 4,5-trans-double bond of sphingosine occurrs at the DHCer level (363) as shown in Figure 4, but this was ignored for many years by textbooks (and even today by metabolic pathway wall charts) that showed direct conversion of sphinganine to sphingosine. Desaturation at the DHCer level in vivo was established conclusively by pulse chase labeling studies, (294) and confirmed by development of an in vitro assay for this highly labile enzyme. (364) DHCer desaturases were then cloned from plants, (365, 366) leading to the subsequent identification of the desaturase genes from many organisms, including humans. (367-370) The two mammalian desaturases, DES1 and DES2, appear to have different functions, for DES1 to add the 4,5-trans double bond to make Cer, (367) and DES2 to hydroxylate DHCer at position 4 to produce the t18:0 backbone of phytoceramides. (368-370)

DES activity is influenced by the alkyl chain length of the sphingoid base and fatty acid, the stereochemistry of the sphingoid base (d-erythro versus l-threo-dihydroceramides), the nature of headgroup, and the ability to utilize alternative reductants. (364) Introduction of the 4,5-double bond can be analyzed using NBD-DHCer, which reveals interesting features about the stereoselectivity of the reaction and subsequent metabolism. (371) DES1 is a myristoylated protein and its activity appears to be affected by this post-translational modification. (372)

DES plays a very important role in cell regulation because the signaling targets of Cer typically are not affected by comparable levels of DHCer, which is a sensible mechanism to minimize accidental induction of apoptosis by this intermediate of de novo sphingolipid biosynthesis. (108) DHCer are bioactive, nonetheless, as inducers of autophagy, which surfaced in studies of the mechanisms of action of the anticancer drug fenretinide (4-hydroxyphenyl retinamide, 4HPR) 31. (97) Fenretinide had been thought previously to elevate Cer in studies of how this compound was toxic for numerous human cancer cell lines, (373, 374) both as an inducer of SPT and ceramide synthase. (375) However, when examined by mass spectrometry, the accumulating “Cer” was found to be DHCer, and fenretinide was deduced to inhibit DES, (97) which has been subsequently confirmed. (376) The sphingolipidomic studies that uncovered this novel mechanism of action of fenretinide also revealed that this agent elevated sphingoid bases and sphingoid base 1-phosphates, (97) which have the potential to mediate, or suppress, cancer cell killing, respectively; therefore, follow-up studies examined whether coadministration of a sphingosine kinase inhibitor would enhance the toxicity of fenretinide, and this was found to be the case. (377) Likewise, knockdown of ceramidase has the potential to decrease the production of free sphingoid bases and ameliorate the toxicity of fenretinide, and this too has been found. (378) A large number of inhibitors specifically targeted to DES have also been prepared and characterized. (379-383)

A number of physiological factors have also been found to modulate DES. For example, palmitate (but not oleate) increased mRNA encoding DES1 and Cer biosynthesis, (384) and oxidative stress decreased dihydroceramide desaturase activity in a time- and dose-dependent fashion (and elevated DHCer). (385) A recent comparison of breast cancer cell lines noted that they differed in the relative expression levels of DES1 versus DES2, and follow-up analysis of the sphingolipids of the cells found the correlating differences in Cer versus PhytoCer in the sphingolipids. (290)

The enzymes and genes have not yet been identified for the production of the mammalian sphingoid bases with a second double bond at carbon 14, or for the skin sphingoid base with a hydroxyl at position 6.

Complex Sphingolipid Biosynthesis

In mammals, Cer is at the branchpoint for biosynthesis of four major compounds (Figures 4 and 7): the two phosphosphingolipids, sphingomyelin (SM) and Cer 1-phosphate (Cer-P) and two glycosphingolipids, galactosylceramide (GalCer) and glucosylceramide (GlcCer), which are converted into hundreds of complex glycosphingolipids as discussed above and summarized in an excellent review by Furukawa and colleagues, (386) a comprehensive series of pathway maps prepared by Akemi Suzuki, (387) a web-based hypothetical pathway scheme (www.sphingomap.com), and this review. Pathway maps based on the known genes for these pathways have also been developed for use with gene expression data sets. (290, 388) In addition, two more headgroups have been found to be produced by mammals, ceramide phosphoethanolamine (153) and 1-O-acylceramide, (389) but in such small amounts that they have not been included in Figure 4 or 7.

Figure 7. A scheme depicting the major headgroup additions to (dihydro)ceramides and subsequent metabolites that define the different categories (including root structure series) of more complex sphingolipids. Ceramides and dihydroceramides (one of which is depicted in the octagon at one o’clock in this diagram) are converted into sphingomyelin (SM), ceramide 1-phosphate (CerP), glucosylceramide (GlcCer), and galactosylceramide (GalCer), then to downstream metabolites as shown (see text). Ceramide phosphoethanolamine and 1-O-acyl-ceramides are not shown because they appear in mammalian cells in trace amounts. Each enclosed section represents a subcategory of glycosphingolipid, such as ST for sulfatides (red circles, as in Figure 4) (note that some of the sulfated glycosphingolipids fall into both the GalCer, that is, Gala, subcategory and others are derivatives of GlcCer). The arrow to the isoglobo family is less bold because that enzyme is not thought to be active in humans. The key for the symbols and coloring scheme is the same as in Figure 1 the earlier figures.

Sphingomyelin, Ceramide Phosphoethanolamine, and Ceramide Phosphate

Cer is metabolized to SM in the Golgi (390, 391) and plasma membrane (392, 393) by SM synthases that catalyze the transfer of phosphorylcholine from phosphatidylcholine to the 1-hydroxyl of Cer with the liberation of diacylglycerol, (394, 395) with SMS1 localized to the Golgi, and SMS2 localized to the plasma membrane. (396) Because SM biosynthesis occurs at multiple sites and by more than one enzyme, as well as involves trafficking of the precursor Cer by more than one mechanism, it can be a difficult process to study. (397) This is probably also a manifestation of the multiple roles that these metabolites (SM, Cer and diacylglycerols) play in plasma membrane signaling. (27) A substantial number of studies have explored the biosynthesis and turnover of SM in cell signaling and disease, as reviewed recently by Hannun and colleagues. (27, 28, 31) A useful tool in studies of SM synthesis has been the inhibitor D609 32. (398)

SMS2 knockout and SMS2 liver-specific transgenic mice have been prepared (399) and both had lower plasma SM than wild-type mice under usual dietary conditions, but differed when fed with high fat diets. (399) The SMS2 knockout mouse has also shown attenuated lung injury in response to lipopolysaccharide (400) and reduced atherogenesis, (401) among other interesting phenotypes.

Ceramide phosphoethanolamine biosynthesis involves the analogous transfer of the phosphoethanolamine group from phosphatidylethanolamine to Cer, which was first noted with microsomes and plasma membranes from rat brain and liver (393) (also with subsequent methylation using S-adenosylmethionine to produce SM). (402) The enzymes responsible for ceramide phosphoethanolamine biosynthesis have been reported to be a specific transferase, SMSr, that has only ceramide phosphoethanolamine synthase activity, and SMS2, which appears to be bifunctional enzyme that synthesizes both SM and ceramide phosphoethanolamine. (153) SMSr catalyzes the synthesis of ceramide phosphoethanolamine in the lumen of the endoplasmic reticulum, but in only trace amounts, and has been speculated to play a role in Cer homeostasis because blocking its catalytic activity causes a substantial rise in Cer. (154)

The other phosphosphingolipid made by mammals is ceramide 1-phosphate, which is produced by ceramide kinase (CERK) and possibly other yet-to-be-discovered enzymes because CERK knockout does not completely eliminate these compounds. (403) CERK is selective for Cer with a minimum fatty acyl chain length of 12 carbons, and the 4,5-trans double bond of the sphingoid base backbone is important for substrate recognition. (404) The production of ceramide 1-phosphate has been implicated in cell proliferation and survival, (405) and activation of the cytosolic phospholipase A2 (cPLA2) for inflammatory signaling. (406) KNVP-231 33 is a specific and reversible CerK inhibitor that is active in the low nanomolar range and useful in studies of this metabolic step. (407)

One of the factors that governs the biosynthesis of both SM and Cer1P is the delivery of Cer to the enzyme by a Cer transport protein (CERT) discovered by Hanada and co-workers. (408, 409) CERT mediates the ER-to-Golgi trafficking of ceramide, (410) and appears to act at membrane contact sites between the ER and the Golgi apparatus. (411)

CERT most efficiently transfers Cer having C14- to C20- chain lengths (but not longer alkyl chains) as well as C16-dihydro- and phyto-Cer. (412) N-(3-Hydroxy-1-hydroxymethyl-3-phenylpropyl)dodecanamide (HPA-12 34) (see comment on stereochemistry) (413) inhibits ceramide trafficking by CERT. (414)

Other Non-Glycan Headgroups

The other known category of nonglycan headgroup modification by mammals is O-acylation, (389) which has been shown to be due to a group XV calcium-dependent, lysosomal phospholipase A that has the unique ability to transacylate short chain ceramides. It is highly expressed in alveolar macrophages, and mice lacking this enzyme develop a phenotype similar to human autoimmune disease. (415)

Glycosphingolipids

The core concepts for how cells biosynthesize hundreds of different headgroup categories of glycosphingolipids are summarized in Figures 7 and 8. Basically, the stage is set by there being a limited number of initial glycosyltransferases (mammals only add glucose and galactose directly to Cer even though several other types of carbohydrates are utilized later), followed by one major product from GlcCer (addition of Gal to form LacCer), then generation of further diversity by expansion to the root structure categories summarized in Figure 1. The Gala series (i.e., from GalCer) is simpler, although it contains somewhat more components than are illustrated in Figure 7 (such as the sulfated glucuronoglycolipids, which will be described later).

Glycosphingolipid biosynthesis (and especially ganglioside biosynthesis) has been referred to as a “combinatorial” process (14) because it produces many products from relatively few reactions (catalyzed by the glycosyltransferases) that are able to utilize a toolkit of precursors and intermediates to produce an ensemble of products. To a certain degree, the nature of the products are predictable based on the specificities of the enzymes, their locations, and the localization, amounts and types of the cosubstrates; however, since most of the components are membrane associated, all possibilities are not necessarily produced in detectable amounts.

The glycosyltransferases often transfer a specific carbohydrate from the appropriate sugar nucleotide (e.g., UDP-Glc, UDP-Gal, CMP-sialic acid) to a specific position on a particular type of acceptor (Cer or to the nonreducing end of the growing carbohydrate chain attached to Cer). For most of the enzymes presented in this review, sphingolipids are the preferred acceptors. (386) In large part, the structure feature of the acceptor that is recognized is the carbohydrate portion, however, there are instances where the backbone has been noted to be a factor, such as in the partitioning of α-hydroxy-Cer into downstream glycosphingolipids. (416)

Biosynthesis of GlcCer

GlcCer are synthesized by UDP-Glc:Cer glucosyltransferase (alternatively called GlcCer synthase and abbreviated GCS, UGCG and CGlcT-1), (417) and the only mechanism to produce GlcCer appears to be via this gene product based on studies with a mouse melanoma cell line (GM-95 cells) with mutated GCS. (418) Studies with this cell line have been very informative about the effects of eliminating GlcCer and downstream glycosphingolipids, which slowed their growth rate and altered cell morphology, (418) although the cells retained the ability to adhere to extracellular matrix (ECM) proteins such as fibronectin, collagen, and laminin. (419) Elimination of this enzyme in mice with a null mutation (420) was embryonic lethal, but embryogenesis proceeded well into gastrulation with differentiation into primitive germ layers and patterning of the embryo before death.

GlcCer biosynthesis can be blocked by inhibitors of this enzyme, (421) and when applied to mouse knockout model of Fabry disease (where a deficiency of the enzyme α-galactosidase causes Gb3 to accumulate), inhibitor treatment blocked accumulation of Gb3 in the kidney, liver, and heart without significant changes in body weight or organ weight, which was suggestive that such compounds might be promising as therapeutic agents for the treatment of glycosphingolipid storage disorders. The most recent generation of inhibitors of GlcCer synthase is (1R,2R)-nonanoic acid[2-(2′,3′-dihydro-benzo [1,4] dioxin-6′-yl)-2-hydroxy-1-pyrrolidin-1-ylmethyl-ethyl]-amide-L-tartaric acid salt (Genz-123346) 35. (422) This compound has also shown efficacy in mouse models for Fabry disease, (423) Gaucher disease (where there is accumulation of GlcCer due to defective lysosomal glucocerebrosidase/acid β-glucosidase), (424) and polycystic kidney disease, a family of genetic disorders characterized by renal cystic growth and progression to kidney failure. (425)

Use of GlcCer synthase inhibitors has revealed how decreases in cellular levels of neutral glycosphingolipids and gangliosides (and elevation of Cer) causes cell cycle arrest, (426) and how GlcCer synthesis appears to be a major determinant of survival of tumor cells. (427, 428) They also led to identification of a previously unknown pathway for ceramide metabolism, the formation of 1-O-acylceramide via a phospholipase A2. (415, 429)

Biosynthesis of LacCer

GlcCer is next glycosylated to Galβ1–4Glcβ1Cer (LacCer) by two LacCer synthases (β4-galactosyltransferases), β4GalT-V and -VI, (430) with the former also being implicated in the synthesis of N-glycans of cell surface glycoproteins. (183) Before this can occur, however, the GlcCer must flip to the inside of the Golgi because GlcCer is made on the cytosolic aspect of the ER or early Golgi membranes, (431, 432) whereas LacCer and more complex glycosphingolipids are made in the lumen of the Golgi apparatus. (433) Studies with rat liver ER and Golgi membranes have found that transbilayer movement of spin-labeled GlcCer is rapid, saturable, and inhibitable by protease treatment, which suggests that the membranes contain a GlcCer flippase. (434) The mechanics of GlcCer delivery to the sites of higher glycolipid biosynthesis appears to be more complex than just flipping across the membrane because after GlcCer is made on the cytosolic leaflet of the Golgi, it is transported back into the ER (via Golgi-associated four-phosphate adaptor protein 2, FAPP2) before achieving access to the lumen of the Golgi. (435, 436) FAPP2 is a dimeric protein that has the capability to form tubules from membrane sheets (an activity that is dependent on the phosphoinositide-binding activity of the PH domain of FAPP2) and it has been suggested that FAPP2 functions directly in the formation of apical carriers in the trans-Golgi network. (437, 438)

Some of the factors that have been reported to regulate LacCer synthase include growth factors, cytokines, lipids, lipoproteins, and hemodynamic factors, such as fluid shear stress. (439)

Biosynthesis of Ganglio-Series Glycosphingolipids

As shown in Figure 7, one of the fates of LacCer is conversion to the neutral and acidic members of the ganglio-root structure series glycosphingolipids (blue bordered box in Figure 7). The enzyme responsible for the first neutral metabolite GalNAcβ1–4Galβ1–4Glcβ1Cer (GA2, also called asialo-GM2) is GM2 synthase, which is also called β4GalNAcT, β1,4-N-acetylgalactosylaminyltransferase and GM2/GD2 synthase because it additionally converts gangliosides GM3 to GM2, GD3 to GD2, etc., as shown in Figures 7 and 8. (440) Therefore, this enzyme is critical for synthesis of all complex gangliosides enriched in the nervous system of vertebrates (GM1a, GD1a, GD1b, GT1b, GQ1b, etc.), as well as downstream neutral (asialo-) glycosphingolipids (GA1), which has been confirmed by studies with the knockout mouse. (386, 441) Interestingly, knockout of this gene did not affect brain morphology/histology, but there were effects on the maintenance and repair of nervous tissues, differentiation of spermatocytes, and regulation of interleukin-2 receptor complex.

The other major branch of metabolism of LacCer is its sialylation to ganglioside GM3 (Figures 7 and 8) by ST3Gal-V (SAT-I, CMP-N-acetyl-neuraminate:lactosylceramide α2,3-sialyltransferase, GM3 Synthase). (442) GM3 null mice are unable to synthesize GM3, as anticipated, and appear to be without major abnormalities, but have a greater sensitivity to insulin due to enhanced insulin receptor phosphorylation in skeletal muscle, are protected from high-fat diet-induced insulin resistance, (443) and have impaired hearing due to selective degeneration of the stereocilia of hair cells in the organ of Corti. (444) The relationship between GM3 and insulin signaling is provocative because it might provide better insight into type 2 diabetes, and it has been suggested that this involves interactions between insulin receptors and gangliosides in membrane microdomains, and might be a new paradigm for insulin receptor regulation. (444) Defects in GM3 synthase have also been found clinically, (445) wherein a nonsence mutation in the gene that would cause a premature termination caused loss of activity, GM3 and its derivatives, and developmental stagnation and blindness.

Figure 8. Representative reactions of ganglioside biosynthesis. An illustration of the “combinatorial” nature of ganglioside biosynthesis by the indicated glycosyltransferases (note alternatives names for each enzyme). The key is the same as in Figure 1.

The other downstream metabolites in this pathway shown in Figures 7 and 8 are formed by analogous reactions, for example, GA2 is converted to GA1 by β3GalT-IV (also called GM1 synthase, β3GalT, and Gal-T2), (446) which can be in turn sialylated to ganglioside GM1b by GT1b/GD1a/GM1b synthase (also named ST3Gal-II, SAT-IV, CMP-N-acetylneuramininate: d-galactosyl-N-acetyl-d-galactosaminyl-(N-acetylneuraminyl)-d-galactoxyl-d-glucosylceramide α2,3-sialyltransferase). (447) Likewise, to form the disialo- (GD3) and trisialo- (GT3) gangliosides, the additional enzymes GD3 synthase (SAT-II, ST8Sia-I, CMP-N-acetylneuraminate: GM3 α2,8-sialyltransferase) and GT3 synthase (SAT-III) are invoked (with the products of each of these serving as substrates for the enzymes already described to synthesize GD2, GT2, etc., as shown in Figure 8). Thus, the profile of ganglio-series glycolipids that are made by a particular cell will depend on the particular glycosyltransferases that are expressed, their kinetic properties, and other issues such as localization, availability of the substrates, presence of enzymes that may be competing for the same intermediates, and the rates at which the precursors and products are trafficked through the Golgi. (14) As these relationships become better understood, one can begin to make computational predictions about what species will be made based on gene expression profiles and pathway maps, (448) and even predictions about glycan structures from genomic information about glycosyltransferases, (449, 450) although the outcomes still require experimental verification.

A reaction not shown in these diagrams is the addition of fucose to produce compounds such as fucosyl-GM1a shown in Figure 1. This is catalyzed by fucosyltransferases (α1,2-fucosyltransferase 1 and 2, FUT1 and FUT2; (451) α3/4-fucosyltransferase, FUT3, Lewis enzyme; (452) and others). Fucosyl-GM1, which can be made by both FUT1 and FUT2, is expressed in a variety of cancer tissues, and has been considered to be a tumor marker and target for immunotherapy. (453) Aberrant glycosphingolipid profiles are one of the hallmarks of cancer and over forty years ago, Hakomori and Murakami noted that “the structural remodeling of glycolipids and glycoproteins are undoubtedly a key to open a secret box of malignancy.” (454) Largely through the efforts of Sen-Itiroh Hakomori and his many collalborators and trainees, (455) a lot is now known about the links between glycosphingolipids and abnormal cell behavior in cancer, as well as tumor progression, metastasis, and invasivity. (456, 457) The underlying premise has been that some of these compounds might be useful biomarkers, and/or that restoration of a more normal composition might have clinical benefit. This latter idea has been supported, for example, by studies of gliomas, which have lower expression of several sialyltransferases (ST6Gal1, ST6, and ST6GalNAcV), so when U373MG glioma cells were stably transfected with ST6GalNAcV, this increased expression of GM2α and GM3 gangliosides, caused marked inhibition of in vitro invasivity, modified cellular adhesion to fibronectin and laminin, and inhibited tumor growth in vivo. (458) Therefore, the concept that normalization of sphingolipid profiles in cancer could be of therapeutic benefit is very appealing. It is worth mentioning that the links between cancer and glycosphingolipids have not been limited to the headgroups (459) and this also might be useful in identifying more unique biomarkers.

One other category of ganglioside derivative that is not shown in these pathway diagrams is the O-acetylation of the Neu5Ac, which is conducted by a 7- or 9-position sialic acid-specific O-acetyltransferase. (460) An enzyme has also been found that removes the acetyl-group from 9-O-acetyl-sialic acids. (461) There has been considerable interest in 9-O-acetylGD3 because it is found in tumors and appears to protect them from apoptosis. (462)

Regulation of ganglioside expression has been studied fairly extensively, particularly during brain development, where ganglioside biosynthesis switches between expressing simple and complex gangliosides or between different ganglioside series, and the factors that govern this “orchestration of glycosyltransferases” (463) have been reviewed.

Biosynthesis of Lacto-/Neolacto-Series Glycosphingolipids

Biosynthesis of the lacto-/neolacto-series glycosphingolipids begins with the formation of GlcNAcβ1–3Galβ1–4Glcβ1Cer (also referred to as Lc3 or amino-ceramide trihexoside, amino-CTH) by β-1,3-N-acetylglucosaminyltransferase (also named UDP-N-acetylglucosamine: β-galactose β1,3-N-acetylglucosaminyltransferase, amino-CTH synthase or β3GlcNAcT) (Figure 7). This gene has been cloned (464) and the gene named β3Gn-T5. The knockout mouse displays multiple phenotypic changes with some dying in less than 2 months, developing early stage growth retardation, and having shorter lifespan overall. Pathologies include splenomegaly and notably enlarged lymph nodes, fur loss, obesity, and reproductive defects. (203)

The distinction between the lacto- versus neolacto- series glycosphingolipids is determined by the next galactosyltransferases, which are β1,3GalT for Lc4 and β1,4GalT for nLc4 (Figure 7). Lc4 is a precursor for formation of Lewis^a, Lewis^b upon addition of fucoses, and sialyl Lewis^a (by the action of ST3Gal-III), and nLc4 is a precursor for Lewis^x, Lewis^y, and sialyl-Lewis^x (c.f., Figure 2 and Figure 7).

Biosynthesis of Globo-/Isoglobo-Series Glycosphingolipids

Biosynthesis of the Gb3 (Galα1–4Galβ1–4Glcβ1Cer) is catalyzed by Gb3 synthase (α1–4-galactosyltransferase, α1–4GalT), then to Gb4 (via β3GalNAcT), as shown in Figure 7. The next globoside in this series, Gb5 (synthesized by β3GalT-V), is also known as the stage-specific embryonic antigen-3 (SSEA-3), (465) a frequently used stem cell marker. (466) Although iGb3 synthase (α1–3GalT) is shown in Figure 7 by a faint line, the human iGb3 synthase gene contains several mutations that render its product nonfunctional, (201) and this has been supported by in vitro assays. (197)

As noted earlier, globosides have also received much attention as receptors for Shiga toxin, (196) verotoxins, and the HIV adhesin gp120, (10) and for their elevations in cancer (197) and Fabry’s disease. (195)

Biosynthesis of GalCer

GalCer are made by UDP-Gal:Cer galactosyltransferase, also called GalCer synthase or cerebroside synthase, and abbreviated CGT or CGalT (human gene, UGT8). (467) GalCer is synthesized in the lumen of the ER (468) using UDP-Gal that is transported to the lumen of the ER by UDP-Gal transporter 2 (UGT2), a splice variant of UGT1 (the transporter for UDP-Gal into the Golgi) that contains an ER locating dilysine motif. (469) Disruption of the mouse gene produced animals that did not synthesize GalCer or sulfatide but they formed myelin containing glucocerebroside. This did not substitute fully for GalCer, however, because the mice exhibited severe generalized tremoring and mild ataxia, and developed progressive hindlimb paralysis and extensive vacuolation of the ventral region of the spinal cord. (470) Transgenic mice overexpressing the this GalCer synthase had an increase in activity and monogalactosyl diglyceride and nonhydroxy fatty acid-containing GalCer, but the latter was accompanied by a concomitant decrease in α-hydroxylated GalCer; therefore, there must be some mechanism to maintain the total level of GalCer. Nonetheless, the transgenic mice developed progressive hindlimb paralysis and demyelination. (471)

Sulfated Glycosphingolipids

Sulfatides are formed by the transfer of a sulfate to one of the hydroxyls of a glycosphingolipid by using the activated sulfate donor 3′-phosphoadenosine-5′-phosphosulfate (Figure 7). Two of the more thoroughly studied sulfotransferases are 3′-phosphoadenosine 5′-phosphosulfate:galactosylceramide sulfotransferase (GalCer sulfotransferase), which produces 3′-sulfo-galactosylCer, (472) and a sulfotransferase from rat brain (473) that catalyzes the transfer of sulfate to glucuronylglycolipids (GGL), (474) such as GlcAβ1–3Galβ1–4GlcNAcβ1–3Galβl–4Glcβl-Cer to from sulfated glucuronylglycolipids (SGGL), 3′-sulfo-GlcAβ1–3Galβ1–4GlcNAcβ1–3Galβl–4Glcβl-Cer. Mass spectrometry has been helpful in mapping out the metabolic pathways for sulfatides of the ganglio-series. (475) A connection between vitamin K (or warfarin administration) and sulfatide biosynthesis has been suggested by several studies, but the mechanism has been elusive. (476)

The cDNA encoding GalCer sulfotransferase has been cloned, (477) and knockout mice have been generated to analyze the biological roles of sulfoglycolipids and pathophysiology of their deficiency, which included neurological disorders due to myelin dysfunction and amelioration of monocyte infiltration in the kidney after ureteral obstruction, which provides evidence that sulfatide is an endogenous ligand of l-selectin. (478, 479) Studies of sulfatide deficiency have also utilized mice that are genetically deficient in UDP-galactose: ceramide galactosyltransferase because the inability to synthesize galactosylceramide precludes the biosynthesis of sulfatide by sulfation of GalCer (480) and have compared the morphological features between the galactolipid-null and the sulfatide-null mice. (481) Reduced formation of sulfatides has been suggested to play a role in polycystic kidney disease. (482)

Integration of Backbone and Headgroup Biosynthetic Pathways

Figure 9 provides a symbolic representation of sphingolipid biosynthesis de novo from the perspective of both the lipid backbones and the headgroups. (3) Panel A explains the layout for the sphingolipids made from Ser, with the first node representing 3-ketosphinganine; the next, sphinganine; then fanning out to form a ring that represents the ensemble of N-acyl-sphinganines (with the fatty acid chain labeled in blue); from which the different categories of headgroups are added, as indicated in the blow-out in the upper portion of panel A. Thus, each fan blade represents all of the headgroup derivatives for one N-acyl-sphingoid base backbone. Panel B illustrates how this scheme expands as one includes all three types of sphingoid bases made by SPT using Ser (for sphinganine, d18:0), Ala (for 1-deoxysphinganine, m18:0) and Gly (for 1-desoxymethylsphinganine, m17:0). The initial from each of these represent the N-acyl-derivatives followed by headgroup addition, as shown in panel A (note that the blades of the fans for m18:0 and m17:0 do not extend beyond the first ring because neither of these undergo headgroup addition), and the lines that connect the inner rings to the next fans represent the desaturation of the sphingoid base backbones each of these N-acyl-sphingoid bases (e.g., converting DHCer, N-acyl-d18:0, to Cer with an N-acyl-d18:1 backbone, etc.). Also shown are the additional backbones from 4-hydroxylation of DHCer by DES2 to form the t18:0 backbone, and desaturation of Cer to produce the sphingadiene backbone (d18:2) (and others could be added for additional modifications to the sphingoid base chain). The 1-deoxy- and 1-desoxymethyl-sphingoid bases might also undergo these further backbone modifications, but we have not yet seen these products by mass spectrometric analysis of mammalian samples (unpublished observation), so they have not been added to the scheme. For a representation of all of the sphingolipids that can be made de novo, one would display several of these maps, with one for each fatty acyl-CoA that is utilized in the first step (for examples, myristoyl-CoA for the d16:0 sphingoid base chain length; stearoyl-CoA for d20:0, etc.). This type of diagram is mainly useful as a mental exercise to appreciate the pathways that would produce every individual molecular subspecies; however, it might be possible someday to populate it with colored pixels representing the relative amount of each subspecies (or differences in amounts between two sources, as in a gene expression heat map), to facilitate visualization of patterns or interrelationships that would otherwise be difficult to appreciate.

Figure 9. Backbone and headgroup relational depiction of mammalian sphingolipid biosynthesis. This alternative depiction of de novo sphingolipid biosynthesis displays how the pathway can be envisioned to start with a fatty acyl-CoA (palmitoyl-CoA in lower portion of panel A) that is condensed with Ser to form 3-ketosphinganine then sphinganine (at the center of the fan), which is N-acylated to produce different chain-length dihydroceramides (represented by the ring, with examples of chain lengths labeled in blue). Each dihydroceramide subspecies can be converted into families of dihydro-complex sphingolipids, which are symbolized by the blades. The upper portion of panel A shows some of the complex sphingolipids within each wedge (which are only a fraction of the actual number of compounds that can be made, as illustrated by Figures 7 and 8, and the discussion in the text). Panel B displays further complexities related to the lipid backbones. The upper portion of panel B illustrates how the dihydroceramides from each sphingoid base backbone (in this case, d18:0 from palmitoyl-CoA) can be hydroxylated to phytoceramides (t18:0) and/or desaturated to ceramides (d18:1) (c.f., Figure 4); the latter is also presumed to undergo further desaturation to form N-acyl-sphingadienes (d18:2). The blades radiating from each N-acyl-chain subspecies represents the complex sphingolipids, as explained for panel A. The lower portion of panel B shows that Ala or Gly are alternatively used by serine palmitoyltransferase to form m18:0 and m17:0 which are N-acylated and, to some degree, desaturated to N-acyl-m18:1’s and N-acyl-m17:1 (to date, backbone hydroxylation has not been noted). Note that these do not radiate into larger blades because headgroups cannot be added. Not shown are the utilization of other fatty acyl-CoAs, which would constitute parallel schemes like these, nor pathways where sphingolipids are turned over to generate intermediates that are recycled or turned over (although one can envision this occurring within the blades to return to the hub, with the apex of the hub representing the free sphingoid base). The symbols and abbreviations are the same as have been used in the other figures in this Review.

The elements of this scheme occur in discrete (and often multiple) locations in the cell, where particular combinations of the enzymes, cosubstrates, trafficking proteins, etc., make a major contribute to the outcome. Further discussion of this facet of the biosynthetic pathway is beyond the scope of this review, except for the few instances that have been presented with a particular metabolic step, such as the compartmentation of GalCer biosynthesis in the lumen of the ER.

Sphingolipid Turnover, Trafficking, and Recycling

Metabolic homeostasis for the sphingolipidome is achieved by balancing biosynthesis, degradation, recycling, and processes that add exogenous sphingolipids to, and remove them from, the cell. This review is concerned mainly with sphingolipid biosynthesis but will also briefly address these other processes because they are interrelated and should be kept in mind. Metabolic turnover is defined as any process that hydrolyzes a complex sphingolipid to component parts. This usually occurs via lysosomal enzymes (483) and, if the intermediates are not recycled, is followed by the irreversible degradation of the sphingoid base to products that are no longer categorized as sphingolipids (e.g., a fatty aldehyde and ethanolamine phosphate) in the cytosol. (484) Hydrolytic enzymes for sphingolipids are also found in other locations in the cell to produce bioactive products for cell signaling (5, 6) and rearrangement of membrane architecture. (23, 485) The complete balance sheet for sphingolipids additionally includes uptake of sphingolipids from exogenous sources (such as albumin and lipoproteins) (486, 487) and losses by efflux, (488) lipoprotein secretion, (354, 489) and shedding of membrane vesicles containing sphingolipids. (490)

Metabolic Turnover

The major steps in the hydrolysis of complex sphingolipids are summarized in Figure 10, which has the same basic pathway layout as for the other figures for self-consistency. Most of these steps were discovered in the course of understanding genetic diseases that had been noted to involve accumulation of a particular category of sphingolipid. (483) As the lysosomal hydrolases were characterized and in some cases found not to be mutated despite the appearance of disease symptoms in some of the patients, accessory proteins (such as GM2 activator protein shown in Figure 10) were found also to be important. In addition to these, one disease that appeared to be due to defective sphingolipid turnover, Niemann–Pick type C disease (due to accumulation of sphingomyelin, although that was erratic), was found not to be due to a genetic defect in an enzyme of sphingomyelin metabolism but rather a lipid transporter that affects multiple categories of lipids. (491) If the reader is interested in more information about the diseases resulting from defects in sphingolipid metabolism, at least three outstanding reviews of that topic have been published recently. (295, 483, 492)

Figure 10. Sphingolipid turnover and catabolism. Representative enzymes and intermediates are shown for the turnover of each complex sphingolipid family to the lipid moiety (Cer), and the insert displays the degradation of the sphingoid base by phosphorylation and lytic cleavage to a fatty aldehyde and ethanolamine phosphate. The symbols and abbreviations are the same as have been used in the other figures in this Review.

Over time, some sphingolipids were found to be hydrolyzed not only by lysosomal enzymes (with acidic pH optima) but also by enzymes with neutral or alkaline pH optima. These include sialidases in the plasma membrane (which are able to modulate cell regulation by gangliosides) (493) and nuclear membranes (the latter apparently to produce GM1 by hydrolysis of GD1a for nuclear function), (494) plasma membrane β-galactosidase and β-glucosidase (which is active without activator proteins and displays a trans activity in living cells), (495) alkaline, (496) and neutral (497, 498) sphingomyelinases as well as multiple ceramidases (at least five human ceramidases encoded by distinct genes: acid, neutral, and three alkaline ceramidase) (499) that have functions from sphingolipid digestion to cell signaling. Therefore, turnover of sphingolipids occurs in a large number of locations: in the extracellular environment (e.g., as in sphingolipid digestion in the lumen of the intestine), on the extracellular and intracellular surfaces of the plasma membrane, and associated with multiple intracellular organelles.

Sphingolipid Trafficking and Membrane Dynamics

The general scheme for sphingolipid biosynthesis and trafficking that has been in place for some time (500, 501) is that Cer is produced de novo in the ER (253) then transported to the cis-Golgi via vesicular trafficking or the trans-Golgi by CERT, (410) where more complex (glyco)sphingolipids are made (with the differential localization of CERK, SM synthases and specific glycosyltransferases influencing the partitioning of the intermediates into the endproducts) (463) and (mostly) delivered to the plasma membrane to enrich it with sphingolipids and cholesterol. (501) This traditional pathway is schematically represented in Figure 11 by black arrows. Other routes of sphingolipid relocation in cells include transbilayer movement by ATP-binding cassette (ABC) family of membrane-bound transporters, (502) which may also be a pathway for efflux of S1P, (503) intermembrane transfer via the Glycolipid Transfer Protein (GLTP) superfamily (504) and other transporters such as MDR2 (P-glycoprotein) and the cystic fibrosis transmembrane regulator (CFTR). (505)

Inward trafficking of sphingolipids is illustrated by the green arrows in Figure 11. This was initially defined as “housekeeping” turnover of sphingolipids via internalization of membrane vesicles that are sorted into components for lysosomal hydrolysis, with the released sphingosine being degraded or recycled as summarized, respectively, in sections and . Cellular membranes additionally enter the lysosomal compartment by autophagy during phagocytosis, (506) which is thought to use autophagy components to facilitate acquisition of lysosomal enzymes by the phagosome. (507-509) Since sphingolipids are components of autophagosomes (and are required for induction of autophagy), (510) they are likely to be hydrolyzed when the autophagosome becomes acidic and acquires lysosomal hydrolases. Retrograde trafficking from the plasma membrane to the Golgi and ER provides another pathway for inward movement of sphingolipids, and has been studied mostly from the perspective of how it provides a mechanism for bacterial toxins that bind glycosphingolipids (e.g., GM1 for cholera toxin; (511) Gb3 for Shiga toxin (512) and verotoxin (513, 514)) to gain access to the ER.

In addition to these processes, there are many interesting and not-yet-fully explained observations that reveal that the metabolism and trafficking of sphingolipids is even more complicated. For examples, it has been noted: that at least one subunit of serine palmitoyltransferase appears in the nucleus and focal adhesions and affects cell morphology; (251) that ceramide synthesis (N-acylation) occurs not only in the ER but to some extent also in mitochondria, (339, 360) a site where Cer production or targeting can induce cell death; (515, 516) that GlcCer destined for glycolipid synthesis appears to be made in the Golgi but is transported back into the ER (via FAPP2) before achieving access to the lumen of the Golgi, (435) apparently because the FAPP proteins are involved in forming a tubular network that effects transport; (437) that cells make GalCer in the lumen of the ER, (468, 517) raising the possibility that slowed trafficking of Cer from the ER to Golgi (and, thus, more time for Cer to flip from the cytosolic to luminal leaflet) might contribute to the elevated biosynthesis of Gala series glycosphingolipids in stressed cells (518) and that enzymes of sphingolipid metabolism are being found in many other regions of the cell, including the nucleus (207) and the outer leaflet of the plasma membrane, where there are “ecto” glycohydrolases (519) and glycosyltransferases, (520) including a recently described ecto-sialyltransferase (ecto-Sial-T2) that is able to sialylate GM3 exposed on the membrane of neighboring cells using CMP-N-acetylneuraminic acid in the extracellular milieu. (521)

Figure 11. Schematic representation of the locations in and outside of the cell where sphingolipids are metabolized and trafficked. The black dashed lines show the traditional biosynthetic pathway beginning with biosynthesis of the lipid backbone in the ER and subsequent trafficking through the Golgi for further metabolism, leading ultimately to movement to the plasma membrane and other parts of the cell via vesicles and transport proteins (e.g., GLTP) or across the membrane via pumps (ABC, etc.). The green arrows reflect inward movement of sphingolipids destined to lysosomes or to the ER via retrograde motion. The red lines represent additional trafficking of sphingolipids; for examples, for autophagosome formation, formation of multivesicular endosomes and multivesicular bodies, and fusion with the plasma membrane as shown.

Other exported (secreted) enzymes include sphingosine kinase, (522, 523) neutral, (524, 525) and acidic (525) ceramidase, and acid sphingomyelinase. (31) Acid sphingomyelinase is a particularly interesting case because it appears to have multiple functions, (526, 527) including to be secreted by cells upon membrane wounding to facilitate endocytosis of the affected region of the membrane, perhaps by inducing membrane curvature. (528) This introduces the third category of trafficking processes, represented by the red arrows in Figure 11, which include vesicle fusion and trafficking, (529) formation of autophagosomes (discussed above) and multivesicular bodies (which have been proposed to provide a mechanism to release autophagosomes via “unconventional” vesicular secretion), (530) release of membrane particles (microvesicles, shed vesicles, exosomes and ectosomes), as well as the endocytotic processes discussed above. Many of these have already been found to involve sphingolipids, such as that Cer modulates the rate of ER to Golgi trafficking, (531) induces autophagy (532) (as also does dihydroceramides), (97) generates dynamic membrane asymmetry for promotion of membrane curvature, (533) and triggers budding of exosome vesicles into multivesicular endosomes. (534) Some of these processes might reflect a specific sorting process, as has been proposed to occur in a subapical compartment or common endosome, (535) or might be a manifestation of the biophysical properties of Cer, or perhaps an indicator of the broader process such as raft formation, (536, 537) with Cer serving as just one of many participants. In any event, these rapidly evolving subjects are very likely to change the way that we think about sphingolipid homeostasis.

Sphingolipid Recycling (Salvage Pathways)

This review has referred only briefly to the reutilization of sphingolipids after they have been turned over to the free sphingoid base or other intermediates, which has been discussed in at least two excellent reviews. (538, 539) This is clearly an aspect that requires attention not only with respect to the contribution of salvage pathways to overall homeostasis but also for its implications for cell signaling studies where exogenous sphingolipids have been added to cells in culture. Studies of the recycling of endogenous sphingolipids is extremely difficult because the precursors that would be used for the labeling (palmitic acid, serine, etc.) are themselves interconnected with numerous other metabolic pathways.

Studies of the fate of exogenously added sphingolipids have found that they are reutilized, but in complicated ways. Complex sphingolipids labeled in the sphingosine backbone are taken up by cells in culture and hydrolyzed and reutilized, but a substantial amount is rereleased into the culture medium, which implies that they receive special handling. (487) This loss to the medium is very intriguing and is consistent with the finding that microvesicles released from cells in culture are enriched in sphingolipids, (540, 541) and more recently that ceramide triggers budding of exosome vesicles into multivesicular endosomes. (534)

Exogenously added short chain (C6-) ceramides are extensively hydrolyzed and reacylated with long-chain fatty acids, (542) and studies with A549 human lung adenocarcinoma cells found that the generation of endogenous long-chain ceramide in response to exogenous C6-Cer was regulated by reactive oxygen species. (543) A comparison of C2- and C6-ceramides found that the former was not hydrolyzed and recycled like the latter, and proposed that this accounts for differences in the ability of these chain length subspecies to induce apoptosis (i.e., C6-Cer is more potent in inducing apoptosis). (544) Other types of exogenous ceramides, such as fluorescent derivatives with the fatty acyl position occupied by a 6-[N-(7-nitro-2,1,3-benzoxadiazol-4-yl)amino]hexanoyl- group (i.e., C6-NBD-), are also readily taken up and converted to more complex sphingolipids (545) (with interesting differences between different stereoisomers and NBD-dihydroceramides and NBD-ceramides). (371) Exogenously added sphingoid bases are rapidly taken up, phosphorylated, (546) acylated (277) and converted to more complex metabolites (92) depending on the structure of the sphingoid base. The story is also complicated (and perhaps even more so) for sphingosine 1-phosphate, which has been shown to be hydrolyzed by the extracellular lipid phosphatase LPP-1, which facilitated uptake of the sphingosine, followed by its intracellular rephosphorylation by sphingosine kinase (SphK1). (547) The Spiegel lab has shown that a similar phosphorylation-dephosphorylation cycle is involved in reutilization of sphingosine in mammalian cells and appears to take place in the endoplasmic reticulum via sphingosine-1-phosphate phosphohydrolase 1 (SPP-1) and sphingosine kinase 2 (SphK2). (548) SPP1 is an endoplasmic reticulum-resident enzyme that specifically dephosphorylates S1P, and its depletion has also been shown to induce ER-stress and autophagy, processes that alter ER/Golgi trafficking. (549)

Taken in concert, one wonders if it is technically feasible to add exogenous sphingolipids to cells and accurately deduce how endogenous sphingolipids behave because they not only follow different membrane trafficking pathways but also possess biological activities that perturb cell behavior. Similar concerns apply to studies using overexpression or knockout of genes for enzymes of the pathway. This is unsettlingly analogous to the Heisenberg uncertainty principle for quantum mechanics, therefore, one might consider referring to it as the “sphingolipid uncertainty principle”.

Analysis of Sphingolipid Metabolism by “Omic” Technologies

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The sphingolipidome is theoretically defined as all of the molecular subspecies of sphingolipids in an organism or other system of interest, and as the discussion above has illustrated, this encompasses a large number of individual molecular species when both headgroup and backbone variation are taken into account. Many types of methods are available for studying sphingolipids; (550) however, sphingolipidomic analyses are usually conducted by mass spectrometry because both the sphingolipid category and molecular subspecies can be determined. But, as is the case for the other omics, current methods actually encompass only a fraction of the members of this family of compounds, therefore, a sphingolipidomic analysis describes compounds within a particular frame of reference (for example, all of the early metabolites of de novo sphingolipid biosynthesis, such as the ones shown in Figure 4). This can, nonetheless, provide very useful information about sphingolipid metabolism, especially when stable isotope-labeled precursors are used to track the newly made metabolites. (551)

Use of Mass Spectrometry for Sphingolipidomics

Mass spectrometry is not a “one size fits all” technology because different categories of compounds form ions more or less readily (and some are difficult to ionize without some degree of decomposition in the ion source, such as loss of sialic acid or dehydration), there are numerous instances where isomeric and isobaric compounds complicate the analysis and require the additional steps (chromatographic separation of GlcCer and GalCer, for example), and other components in the sample can interfere with the analysis by ionization suppression, clogging of columns and electrospray needles, and many other technical glitches. These considerations have been recently discussed from many perspectives. (34, 552-555) In general the major challenges in MS analysis of sphingolipids are (a) to obtain standards both for methods development and to serve as internal standards (at present, these are only available for a small fraction of the known sphingolipid subcategories); (b) to identify extraction conditions where the analytes of interest and selected internal standards are recovered in high yield whether highly polar (gangliosides and S1P), nonpolar (ceramides), vary in chain length and other biophysical features; (c) to develop complementary methods (usually chromatographic) to separate compounds that are not distinguished by MS alone, which includes the usually thought of isomers and isobars as well as occasions where relatively minor isotopomers (e.g., with several natural abundance ¹³C) of a major species overlaps with the m/z of a compound that is present in the biological sample in much lower abundance; (d) to optimize the ionization, fragmentation and detection parameters to gain maximal information from each compound, and to simply comparison of unknowns with the matched internal standards; (e) to have relatively rapid and facile ways to collect and analyze large data sets; and (f) to be able to display the data in ways that enable large amounts of information to be understood as easily and fully as possible.

Ideally, internal standards should have the same structure as the analyte and vary only in m/z—usually as a stable isotopically labeled version; however, this is not practical for lipidomic analysis and suitably selected representatives of subcategories of compounds are used. An internal standard cocktail has been developed by the LIPID MAPS Consortium and is commercially available from Avanti Polar Lipids (Alabaster, AL). It contains uncommon chain-length sphingoid bases (C17) for sphingosine, sphinganine and their 1-phosphates (S1P and Sa1P) and d18:1;C12:0-fatty acid Cer, Cer1P, SM, and mono- and dihexosylCer, and this can be supplemented with additional internal standards, as desired.

In our experience, it is difficult to extract both the nonpolar (e.g., Cer, SM, and hexosylCer) and the more polar sphingolipids (sphingoid base phosphates, Cer1P, etc.) using one solvent protocol; therefore, we divide the sample into two fractions: one that is later split into separate organic and aqueous phases (for the less polar sphingolipids) and one that is never divided into two phases (for the relatively water-soluble sphingolipids). (39) This protocol was subsequently altered to substitute methylene chloride for chloroform in all steps with free sphinogid bases to avoid the possibility of modification of the free amine via formation of carbene in basic conditions. The published extraction protocol gave high recoveries of all subspecies (i.e., SM, hexosylCer and Cer with C12- to C26-fatty acids); however, we have noted that when samples have a large amount of lipid (as is often encountered with plasma, liver and brain), extra effort may be required to redissolve all of the sphingolipids in the final extract in the LC solvent for LC-ESI-MS/MS, resulting in disproportionate losses of the very-long-chain subspecies.

Liquid chromatography (39, 552, 556) is useful not only for the separation of isomeric and isobaric species (such as GlcCer from GalCer), but also tends to reduce ionization suppression. Reversed phase LC (39, 557-559) is used for separations based on the length and saturation of acyl chains (for example, to separate So and Sa), and normal phase LC (39, 220, 557, 560-562) to separate compounds primarily by their headgroup constituents (for example, distinguish Cer, GlcCer, LacCer, globotriaosylceramide, globotetraosylceramide, SM as well as cholesterol, etc.). LC-ESI MS/MS is the most popular analytical tool for sphingolipid analysis (as represented by the applications cited above, and more), (563-567) because sensitivities are on the order of fmol (or less), which allows analysis of small biological samples (such as ∼10⁵–10⁶ cells in culture) while providing a wide dynamic range (typically several orders of magnitude), which allows analysis of both trace metabolites, such as the sphingoid base 1-phosphates and major structural species (SM). Results from a LC-ESI MS/MS method that has been developed following these principles (and the internal standard cocktail available from Avanti Polar Lipids, Alabaster, AL) (39) can be seen in a recent study of the sphingolipids in RAW264.7 cells activated by KDO₂–Lipid A. (510) It warrants comment that thin-layer chromatography has also been combined with MALDI-MS/MS for analysis of some of the difficult to distinguish glycosphingolipids. (568-570)

Although quantitative analyses have most often used electrospray to ionize sphingolipids, (39, 550) other ionization methods have included atmospheric pressure chemical ionization, APCI, (562) desorption electrospray ionization (DESI), (571) as well as MALDI, (572) which is not always thought of as a quantitative method, but can be with the appropriate controls. MALDI has particularly aided the analysis of more complex glycosphingolipids, (573-575) but might also be applied to smaller molecules (which typically have been obscured by background chemical noise from the MALDI matrix ions) new advances in matrix choices and high-pressure sources. (572, 576-580)

Ion separation and mass analysis is most frequently conducted using triple quadrupole or tandem quadrupole-linear ion trap mass analyzers for MS/MS and MSⁿ, (39, 133, 552, 581) respectively, or for higher mass accuracy, time-of-flight (TOF), (582) orbitrap (583) or Fourier transform (FT) instruments; (584-586) ion mobility MS has also been recently applied to sphingolipids. (587) Fragmentation in MS/MS mode is achieved by a number of ways, depending on the type of compounds involved, and include collision induced dissociation (CID) with nitrogen for most applications and, in a novel approach to determine double bond position, ozone; (588) a recent use of the ion trap to favor backbone fragmentation of SM; (39) and electron transfer dissociation (ETD) for analysis of glycans. (589) Analysis of higher glycosphingolipids can also be conducted by removal of the lipid moiety using endoglycoceramidase, (590) followed by analysis of the glycans by mass spectrometric methods used to characterize O- and N-linked glycans from glycoproteins. (591)

Although sphingolipids are complex, many are relatively easily ionized and can be fragmented to ions that allow the sphingoid base and amide-linked fatty acid to be determined; therefore, stable-isotope labeled precursors (such as U–¹³C-palmitate) can be used to follow biosynthesis of the sphingoid base backbone as well as N-acylation. (551) In this example, ¹³C appears in three isotopomers and isotopologues: [M + 16 for the sphingoid base or N-acyl fatty acid, and [M + 32] for both), in addition to the unlabeled species (corrected for the natural abundance ¹³C species). In interpreting the data, one needs also to determine the isotopic enrichment of palmitoyl-CoA (i.e., the fraction with ¹³C- versus endogenous ¹²C-palmitoyl-CoA) and ideally also that for longer chain fatty acyl-CoA’s that are made by desaturation and/or elongation reactions before incorporation into N-acyl-sphingolipids, which is technically feasible by a recently developed method for LC-ESI-MS/MS analysis of fatty acyl-CoAs. (288) This study used 0.1 mM [U–¹³C]palmitate (added as the 1:1 complex with bovine-serum albumin) to try to remain within the concentration usually found in circulation, (592) in an attempt to cause minimal perturbation of the total cellular palmitoyl-CoA because this compound has been shown to affect gene expression, (593, 594) ion transport, (595) and sphingolipid biosynthesis. (294, 296) Nonetheless, even this low amount, which achieved about 50% labeling of the total cellular palmitoyl-CoA, elevated the amount in the cells by about 3-fold. An alternative approach might be to use [¹³C]acetate to label the endogenous palmitoyl-CoA pool, but quantitative analysis of the labeling is more complicated, (596-598) or to use labeled serine, which has the disadvantage that it only shifts the m/z of the labeled sphingolipids by a few amu (not to mention that serine also participates in multiple metabolic pathways). For some applications, it is also useful to add an exogenous sphingolipid that can be tracked because it has an unusual structure, such as an odd chain length or fluorescence tag. (539)

Tissue-Imaging Mass Spectrometry of Sphingolipids

Studies of sphingolipid metabolism in vivo are complicated by the loss of information about histological localization of the compounds of interest after the tissues have been homogenized for extraction and analysis. This can be addressed, in some cases, by a more direct method of analysis that is broadly called “imaging mass spectrometry,” (599) and the specific application described below has been termed “MALDI imaging mass spectrometry.” (600) In this procedure (in general, and as applied to sphingolipids), (601) a tissue (and sometimes an entire animal) (602) is usually frozen and sliced (the thickness varies, but is usually on the order of ∼10 μm), and adjacent sections are often placed on a chilled MALDI plate and a glass slide, so the MALDI image can be compared to the histologic appearance of the tissue using traditional staining. MALDI matrix compound is imbedded in the sample as uniformly and nondisruptively as possible, then a laser beam is moved incrementally across the sample to generate ions and collect MS and sometimes MS/MS spectra for regions ∼50 μm in diameter (larger, and sometimes smaller, regions can be chosen for each spectrum; however, the technique is usually limited to a histological, that is, one or a few cells, rather than a subcellular scale; subcellular analysis requires a different method for generating ions that is under development). (603) MALDI-imaging MS produces thousands of spectra for samples even only 1 mm² which are analyzed using imaging software to locate specific m/z of interest (representing compounds chosen by the user, or other criteria such as abundance, coclustering, and other features), and these are plotted in x,y-space to yield a virtual molecular image of the distribution of the ions, with color coding that reflects different compounds, or displays the relative abundance of a specific ion (in a heat map style). These images can be cross-referenced with adjacent slices to orient where the ions of interest are located with respect to more traditional histological markers.

An approach to enhance the sensitivity of imaging MS has been to use gold nanoparticles in place of the usual MALDI matrix compounds (in a technique called nanoparticle-assisted laser desorption/ionization MS, or nano-PALDI-imaging mass spectrometry). (604, 605) For much higher resolution (<1 μm), secondary ion mass spectrometry (SIMS) has been used, (606) but the high energy of the ion beams causes extensive fragmentation of lipids. This has been circumvented by using a focused buckminsterfullerene (C₆₀) cluster ion beam that is less destructive to the lipids. (603)

This technique is highly informative when applied to lipids. (607, 608) Some of the findings for sphingolipids from application of tissue-imaging mass spectrometry have been: to localize the areas of accumulation of di- and trihexosylceramides in cutaneous biopsies from patients with Fabry’s disease (a study that used both MALDI and SIMS); (609) to profile the normal distribution of lipids within human skin; (610) to characterize the lipid composition of atheroma; (611) to describe the sphingolipids of the human lens with aging; (612) to discover and localize elevated sulfatides in ovarian cancer; (180) to examine the lipids of lung, (613) and lungs infected with C. neoformans and find that specific SM species are associated with neutrophil infiltration at the site of the infection; (614) and to study in some depth the distribution of sphingolipids in brain using MALDI and SIMS imaging MS, (571, 575, 606, 607, 615-618) with the interesting findings including the distinct localization of gangliosides with the d20:1-sphingoid base backbone, (53) and accumulation of GM2 and GA2 in a mouse model for Tay Sachs/Sandhoff disease. (619)

As these examples show, imaging MS has already proven to be useful in identifying specific molecular subspecies and histological locations of sphingolipids under a wide range of normal and abnormal physiologic conditions; therefore, it is reasonable to think that it will become increasingly valuable as a tool for metabolic studies as the technology becomes better refined and there are more research centers with the instruments (and knowledgeable operators). Although they have thus far had only limited use, stable isotope-labeled sphingolipids can be discerned by this form of mass spectrometry, too, so imaging studies can add a dynamic component. There are still limitations with respect to its ability to resolve isomeric and isobaric compounds and to provide absolute quantitation, however, these can be addressed to some extent by using both standard and imaging mass spectrometry as part of the investigation.

Integration of “Omic” Data Sets for a Systems Biology of Sphingolipid Metabolism and Function

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A typical analysis of the major sphingolipids of cells in culture, plasma and other sources using lipidomic methods generally produces hundreds to thousands of data points, and the number will expand by several orders of magnitude when methods are available to look at all of the subspecies, which puts the sphingolipidome on the scale of other omic data sets. Therefore, sphingolipid researchers face the challenge of all “omics” disciplines, to figure out how to handle and visualize such large amounts of data, mine large data sets for relationships that have not been previously seen by more focused approaches, and integrate what has been (and will continue to be) learned by traditional reductionist approaches with the data produced by metabolomic, transcriptomic, and other omic analyses. There are several ways to envision accomplishing these goals, such as to develop relatively facile ways to visualize the information and, ultimately, to develop mathematical models for all of the components of the system.

Visualization Tools

Graphic display is often the most effective way to communicate data, if done cautiously. (620, 621) This is particularly true for large data sets and complex pathways because, as has been well stated by Alan Aderem, Director of the Institute for Systems Biology: “Human minds are incapable of inferring the emergent properties of a system from thousands of data points, but we have evolved to intelligently interpret an enormous amount of visual information” (http://www.systemsbiology.org/technology/data_visualization_and_analysis).

A typical analysis of the major sphingolipids of cells in culture using lipidomic methods will generally produce hundreds to thousands of data points, which puts it on the scale of transcriptomic data sets, where use of heat maps and other types of visualization tools have become commonplace. In heat map format, lipidomic data are often displayed in the order of N-acyl-chain length or summed carbon number, mass (or m/z, if the data are from mass spectrometry), and sometimes divided into lipid subcategories (622) and/or hierarchial clustering. (623)

Several additional visualization schemes have been developed for mammalian sphingolipid metabolism (3) to display all of the molecular subspecies in a pathway format, similar to Figure 4 (as illustrated in Figure 1 from a recent analysis of de novo sphingolipid biosynthesis by activated RAW264.7 cells), (624) or using a platform of pathway tools prepared by LIPID MAPS (http://www.lipidmaps.org/pathways/index.html) that can also show time course data. Other display formats have been prepared for the glycosphingolipids by the Consortium for Functional Glycomics (www.functionalglycomics.org). One report describes a way to extend the visualization of complex sphingolipid pathways via an interactive visualization tool. (625)

An approach that we have found to be useful (290) allows visualization of both transcriptomic and metabolomic data sets using an open access pathway browser, Pathvisio v1.1, (626) and KEGG-style pathway maps (Kyoto Encyclopaedia of Genes and Genomes) that have been updated and expanded for sphingolipid metabolism. (290, 554) In illustrating the use of this tool, microarray data for two breast cancer cell lines (MDA-MB-231 versus MCF7 cells) were compared and based on differences in the apparent differences in mRNA abundances, possible differences in sphingolipid subspecies were made and evaluated by analysis of the sphingolipid compositions of the cells by mass spectrometry. (290) Two of the predicted differences that were thus confirmed were in the nature of the sphingoid bases in the cells, both with respect to chain length (i.e., higher proportions of C16-sphingosine in the cells with the relatively higher expression of SPT3) and 4-hydroxylation (i.e., higher proportions of 4-hydroxysphinganine, phytosphingosine, in the cells with the relatively higher expression of DES2). When data from a wide range of cancer cell lines, tumors and normal tissues were considered, there was a surprisingly high probability of match between the gene expression data and sphingolipid composition (73%), (290) considering that there are multiple mechanisms for regulation of metabolism beyond transcript amount.

A similar approach has been used to compare gene expression data from mouse embryoid bodies versus embryonic stem cells, determined by quantitative real-time PCR (qRT-PCR) with the sphingolipid composition determined by mass spectrometry. (336) And, to take this approach a further step, it was also used to interpret a gene expression data set for ovarian cancer cells obtained by laser capture microdissection (versus normal human ovarian epithelial cells), which led to the prediction that sulfatides are elevated in human ovarian cancer, which was first confirmed by LC-ESI-MS/MS and then the sulfatides were specifically localized to ovarian epithelial carcinoma cells versus the neighboring stromal cells by tissue-imaging MS. (180) This simple integration of two types of “omic” technologies (“transcriptomics” to direct “sphingolipidomics”) could facilitate the discovery of new facets of how sphingolipid metabolism is regulated, relationships between sphingolipid metabolism and disease, and possibly the identification of new biomarkers.

Mathematical Modeling

Mathematical modeling of metabolic pathways and functions is a rapidly developing science, (627) but is difficult to apply to the sphingolipidome because the pathways are not only complex but still have many yet-to-be-discovered elements. The most comprehensive attempts toward this objective, to date, have been made with yeast Saccharomyces cerevisiae because its sphingolipid biosynthetic pathway has fewer genes and metabolites. (628-630) The models appear to be compatible with the available information about gene expression levels, the kinetic properties of the enzymes, metabolite amounts, etc. (628-630) and how perturbations, such as drugs, (631) heat stress, carbon source utilization, sporulation, cell wall integrity, and others affect this system. (632) A combined integrative analysis of genomic, transcriptomic and lipidomic data revealed a signaling role for phytosphingosine-1-phosphate in regulating genes required for mitochondrial respiration. (633) Mathematical modeling has also been applied to Cryptococcus neoformans to explore sphingolipid metabolism in the organism under acidic conditions with the goal of better understanding fungal pathogenesis. (634) The applicability of this approach to other organisms has also been discussed, (635, 636) and attention has been given to the more complex glycomes (“systems glycobiology”). (637)

Two other mathematical approaches have been applied to data sets from studies of mammalian sphingolipid biosynthesis. One used model-reference adaptive control (MRAC) to investigate the dynamics of de novo sphingolipid synthesis by Hek cells stably transfected with serine palmitoyltransferase, and the MRAC simulations produced results that were comparable to simulations from a standard model using mass action kinetics, and suggested that there might be adaptive feedback from increased metabolite levels. (638) The other approach integrated lipidomics and transcriptomics data collected by the LIPID MAPS Consortium (www.lipidmaps.org) for RAW264.7 cells using a two-step matrix-based approach wherein the rate constants obtained from the first step were further refined using generalized constrained nonlinear optimization. (639) The primary focus of the analysis was the C16-ceramide backbone species, and the resulting model fit the experimental data, with the robustness of the model being validated through parametric sensitivity analysis.

Such efforts will not only provide a better understanding about how these molecules are made and function, but also, to help interpret (and ultimately predict) the outcomes of changes in precursors, effects of inhibitors, genetic mutations, etc. In addition, as has been noted by Voit et al., (636) it also allows the investigator to test one’s “intuitive grasp of the system through simulation studies that represent What-If scenarios.” These are useful not only to test the model, but also to direct researchers toward potentially interesting directions for future investigation.

Perspective on the Current State of Sphingolipid Research

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Research discoveries over the last several decades have, to a substantial extent, transformed sphingolipids from enigmas into intricate puzzles within the ultimate puzzle of life. And unlike an enigmatic riddle, which is usually perplexing until a simple (and retrospectively obvious) answer is found, puzzles are hard to understand until most of the pieces are in place. Finding all the sphingolipid pieces and their places is still a daunting task, but this quest is part and parcel of the omics/systems biology era. One looks forward with great expectations, and curiosity, for what will be understood next.

Author Information

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Corresponding Author
- Alfred H. Merrill - Schools of Biology, Chemistry and Biochemistry, and the Petit Institute for Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, Georgia 30332-0230, United States ; Email: [email protected]

Biography

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Acknowledgment

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This chapter draws heavily on ideas that the author has absorbed from laboratory colleagues (students and postdoctoral fellows, long-time associate Elaine Wang, and collaborators M. Cameron Sullards and May Wang), and gleaned from works by, and fruitful conversations with, Tony Futerman, Yusuf Hannun, Konrad Sandhoff, Walt Shaw, Jim Shayman, Sarah Spiegel, Akemi Suzuki and too many other experts on the topics to cite them adequately. Therefore, heartfelt thanks are due to them all, as well as to the reviewers of this manuscript for Chemical Reviews. Any errors are, of course, the author’s fault. Support from the NIH is gratefully acknowledged (NIH GM069338 “Lipid Maps,” GM76217 and CA137812), as is the Smithgall Institute endowment for the chair in Molecular Cell Biology at Georgia Tech that has facilitated some of the studies described herein.

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Prostaglandins & Other Lipid Mediators (2005), 77 (1-4), 15-22CODEN: POLMFL; ISSN:1098-8823. (Elsevier B.V.)
A review. It has become abundantly clear over the past decade that sphingolipids and their metabolites are key signaling mols. Ceramide, the backbone of all sphingolipids, predominantly inhibits cell growth and induces apoptosis, while its metabolite, sphingosine-1-phosphate promotes growth and survival. Given the interconvertibility of these two opposing signaling mols., it is essential that any study that examines the effects of one also look at the other. The newly available technol. of liq. chromatog.-tandem mass spectroscopy (LC-MS/MS) is increasingly being applied for this purpose, as it can quickly identify and measure many different sphingolipids simultaneously. An added benefit of LC-MS/MS is that it is several orders of magnitude more sensitive than enzymic methods or more traditional chromatog. techniques, allowing smaller sample sizes and increased throughput. Here, we briefly discuss the importance of LC-MS/MS for measuring sphingolipid metabolites and some future directions researchers may take given the increasingly accessibility to this technol.
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Karlsson, K. A. Chem. Phys Lipids 1970, 5, 6
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Karlsson, K. A. Lipids 1970, 5, 878
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Shaner, R. L.; Allegood, J. C.; Park, H.; Wang, E.; Kelly, S.; Haynes, C. A.; Sullards, M. C.; Merrill, A. H., Jr. J. Lipid Res. 2009, 50, 1692
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Quantitative analysis of sphingolipids for lipidomics using triple quadrupole and quadrupole linear ion trap mass spectrometers
Shaner, Rebecca L.; Allegood, Jeremy C.; Park, Hyejung; Wang, Elaine; Kelly, Samuel; Haynes, Christopher A.; Sullards, M. Cameron; Merrill, Alfred H., Jr.
Journal of Lipid Research (2009), 50 (8), 1692-1707CODEN: JLPRAW; ISSN:0022-2275. (American Society for Biochemistry and Molecular Biology, Inc.)
Sphingolipids are a highly diverse category of bioactive compds. This article describes methods that have been validated for the extn., liq. chromatog. (LC) sepn., identification and quantitation of sphingolipids by electrospray ionization, tandem mass spectrometry (ESI-MS/MS) using triple quadrupole (QQQ, API 3000) and quadrupole-linear-ion trap (API 4000 QTrap, operating in QQQ mode) mass spectrometers. Advantages of the QTrap included: greater sensitivity, similar ionization efficiencies for sphingolipids with ceramide vs. dihydroceramide backbones, and the ability to identify the ceramide backbone of sphingomyelins using a pseudo-MS3 protocol. Compds. that can be readily quantified using an internal std. cocktail developed by the LIPID MAPS Consortium are: sphingoid bases and sphingoid base 1-phosphates, more complex species such as ceramides, ceramide 1-phosphates, sphingomyelins, mono- and di-hexosylceramides, and these complex sphingolipids with dihydroceramide backbones. With minor modifications, glucosylceramides and galactosylceramides can be distinguished, and more complex species such as sulfatides can also be quantified, when the internal stds. are available. LC ESI-MS/MS can be utilized to quantify a large no. of structural and signaling sphingolipids using com. available internal stds. The application of these methods is illustrated with RAW264.7 cells, a mouse macrophage cell line. These methods should be useful for a wide range of focused (sphingo)lipidomic investigations.
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Quehenberger, O.; Armando, A. M.; Brown, A. H.; Milne, S. B.; Myers, D. S.; Merrill, A. H.; Bandyopadhyay, S.; Jones, K. N.; Kelly, S.; Shaner, R. L.; Sullards, C. M.; Wang, E.; Murphy, R. C.; Barkley, R. M.; Leiker, T. J.; Raetz, C. R.; Guan, Z.; Laird, G. M.; Six, D. A.; Russell, D. W.; McDonald, J. G.; Subramaniam, S.; Fahy, E.; Dennis, E. A. J. Lipid Res. 2010, 51, 3299
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Lipidomics reveals a remarkable diversity of lipids in human plasma
Quehenberger, Oswald; Armando, Aaron M.; Brown, Alex H.; Milne, Stephen B.; Myers, David S.; Merrill, Alfred H.; Bandyopadhyay, Sibali; Jones, Kristin N.; Kelly, Samuel; Shaner, Rebecca L.; Sullards, Cameron M.; Wang, Elaine; Murphy, Robert C.; Barkley, Robert M.; Leiker, Thomas J.; Raetz, Christian R. H.; Guan, Ziqiang; Laird, Gregory M.; Six, David A.; Russell, David W.; McDonald, Jeffrey G.; Subramaniam, Shankar; Fahy, Eoin; Dennis, Edward A.
Journal of Lipid Research (2010), 51 (11), 3299-3305CODEN: JLPRAW; ISSN:0022-2275. (American Society for Biochemistry and Molecular Biology)
The focus of the present study was to define the human plasma lipidome and to establish novel anal. methodologies to quantify the large spectrum of plasma lipids. Partial lipid anal. is now a regular part of every patient's blood test and physicians readily and regularly prescribe drugs that alter the levels of major plasma lipids such as cholesterol and triglycerides. Plasma contains many thousands of distinct lipid mol. species that fall into six main categories including fatty acyls, glycerolipids, glycerophospholipids, sphingolipids, sterols, and prenols. The physiol. contributions of these diverse lipids and how their levels change in response to therapy remain largely unknown. As a first step toward answering these questions, we provide herein an in-depth lipidomics anal. of a pooled human plasma obtained from healthy individuals after overnight fasting and with a gender balance and an ethnic distribution that is representative of the US population. In total, we quant. assessed the levels of over 500 distinct mol. species distributed among the main lipid categories. As more information is obtained regarding the roles of individual lipids in health and disease, it seems likely that future blood tests will include an ever increasing no. of these lipid mols.
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Tanaka, K.; Yamada, M.; Tamiya-Koizumi, K.; Kannagi, R.; Aoyama, T.; Hara, A.; Kyogashima, M. Glycoconj. J. 2011, 28, 67
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Systematic analyses of free ceramide species and ceramide species comprising neutral glycosphingolipids by MALDI-TOF MS with high-energy CID
Tanaka, Kouji; Yamada, Masaki; Tamiya-Koizumi, Keiko; Kannagi, Reiji; Aoyama, Toshifumi; Hara, Atsushi; Kyogashima, Mamoru
Glycoconjugate Journal (2011), 28 (2), 67-87CODEN: GLJOEW; ISSN:0282-0080. (Springer)
Free ceramides and glycosphingolipids (GSLs) are important components of the membrane microdomain and play significant roles in cell survival. Recent studies have revealed that both fatty acids and long-chain bases (LCBs) are more diverse than expected, in terms of i) alkyl chain length, ii) hydroxylation and iii) the presence or absence of double bonds. Electrospray ionization mass spectrometry and matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) have been well utilized to characterize sphingolipids with high throughput, but reports to date have not fully characterized various types of ceramide species such as hydroxyl fatty acids and/or trihydroxy-LCBs of both free ceramides and the constituent ceramides in neutral GSLs. We performed a systematic anal. of both ceramide species, including LCBs with nona-octadeca lengths using MALDI-TOF MS with high-energy collision-induced dissocn. (CID) at 20 keV. Using both protonated and sodiated ions, this technique enabled us to propose general rules to discriminate between isomeric and isobaric ceramide species, unrelated to the presence or absence of sugar chains. In addn., this high-energy CID generated 3,5A ions, indicating Hex1-4Hex linkage in the sugar chains. Using this method, we demonstrated distinct differences among ceramide species, including free ceramides, sphingomyelins, and neutral GSLs of glucosylceramides, galactosylceramides, lactosylceramides, globotriaosylceramides and Forssman glycolipids in the equine kidneys.
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Nature of ceramide in bovine milk
Fujino, Y.; Fujishima, T.
Journal of Dairy Research (1972), 39 (1), 11-14CODEN: JDRSAN; ISSN:0022-0299.
Milk was added to 4% Cl3CCO2H and the ppts. were centrifuged, lyophilized, and extd. with CHCl3-MeOH. The total lipid obtained was chromatographed on silicic acid and the eluted fraction was treated with 0.4N KOH in MeOH and rechromatographed. The lipid in the eluted fraction was recrystd. from ether to purify the ceramide. The Rf value of the single spot obtained from thin-layer chromatog. on silicic acid and the ir spectrum agreed with that of a std. prepn. Sixteen component fatty acids were found upon hydrolysis of the ceramide, among which C23:0 (38.1%), C24:0 (29.5%), C22:0 (17.9%), and C16:0 (7.2%) were predominant. Seven component long-chain bases were detected. The principal bases were C18-sphingosine (35.0%) and C16-sphingosine (31.6%).
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Kyogashima, M.; Tadano-Aritomi, K.; Aoyama, T.; Yusa, A.; Goto, Y.; Tamiya-Koizumi, K.; Ito, H.; Murate, T.; Kannagi, R.; Hara, A. J. Biochem. 2008, 144, 95
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Chemical and apoptotic properties of hydroxy-ceramides containing long-chain bases with unusual alkyl chain lengths
Kyogashima, Mamoru; Tadano-Aritomi, Keiko; Aoyama, Toshifumi; Yusa, Akiko; Goto, Yoshiko; Tamiya-Koizumi, Keiko; Ito, Hiromi; Murate, Takashi; Kannagi, Reiji; Hara, Atsushi
Journal of Biochemistry (2008), 144 (1), 95-106CODEN: JOBIAO; ISSN:0021-924X. (Japanese Biochemical Society)
We analyzed four types of free ceramides (Cer 1, Cer 2, Cer 3 and Cer 4) from equine kidneys by electrospray ionization mass spectrometry. Cer 1 was composed of dihydroxy long-chain bases (dLCBs) of (4E)-sphingenine (d18:1), sphinganine and non-hydroxy fatty acids (NFAs); Cer 2 was composed of trihydroxy LCBs (tLCBs) of 4-hydroxysphinganine, t16:0, t18:0, t19:0 and t20:0, and NFAs; Cer 3 was composed of dLCBs, d16:1, d17:1, d18:1, d19:1 and d20:1, and hydroxy FAs (HFAs); and Cer 4 was composed of tLCBs, t16:0, t17:0, t18:0, t19:0 and t20:0, and HFAs. The results indicate all ceramide species contg. LCBs with non-octadeca lengths (NOD-LCBs) can be classified into hydroxy-ceramides since these species always consist of tLCBs, and/or HFAs. Furthermore, such species tend to contain FAs with longer acyl chains but contain neither palmitate (C16:0) nor its hydroxylated form (C16:0h). The apoptosis-inducing activities of these hydroxyl-ceramides towards tumor cell lines were compared with that of non-hydroxy-ceramides, dLCB-NFA (Cer 1). Monohydroxy-ceramides, tLCB-NFA (Cer 2) and dLCB-HFA (Cer 3), exhibited stronger activities, whereas dihydroxy-ceramides, tLCB-HFA (Cer 4), exhibited similar or weaker activity than dLCB-NFA (Cer 1), depending on cell lines.
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Ogawa-Goto, K.; Funamoto, N.; Abe, T.; Nagashima, K.
Journal of Neurochemistry (1990), 55 (5), 1486-93CODEN: JONRA9; ISSN:0022-3042.
Ganglioside anal. of human motor and sensory nerves revealed that ceramide compns. of sensory nerve GD1a, GD1b, and GM1 apparently differed from those in the motor nerve. These gangliosides from sensory nerve contained a large amt. of long-chain fatty acids and C18-sphingosine as a major long-chain base. On the contrary, the motor nerve gangliosides contained C16-18 fatty acids and a large amt. of d20:1 besides C18-sphingosine. Furthermore, these gangliosides were enriched more in the axon fraction than in the myelin fraction. LM1, which was a major ganglioside in myelin from human peripheral nerve, was composed of similar ceramide compns. in the 2 nerves. Apparently, the characteristic ceramide species of nerve gangliosides may reflect in part properties of their own neurons.
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Imaging mass spectrometry technology and application on ganglioside study; visualization of age-dependent accumulation of C20-ganglioside molecular species in the mouse hippocampus
Sugiura Yuki; Shimma Shuichi; Konishi Yoshiyuki; Yamada Maki K; Setou Mitsutoshi
PloS one (2008), 3 (9), e3232 ISSN:.
Gangliosides are particularly abundant in the central nervous system (CNS) and thought to play important roles in memory formation, neuritogenesis, synaptic transmission, and other neural functions. Although several molecular species of gangliosides have been characterized and their individual functions elucidated, their differential distribution in the CNS are not well understood. In particular, whether the different molecular species show different distribution patterns in the brain remains unclear. We report the distinct and characteristic distributions of ganglioside molecular species, as revealed by imaging mass spectrometry (IMS). This technique can discriminate the molecular species, raised from both oligosaccharide and ceramide structure by determining the difference of the mass-to-charge ratio, and structural analysis by tandem mass spectrometry. Gangliosides in the CNS are characterized by the structure of the long-chain base (LCB) in the ceramide moiety. The LCB of the main ganglioside species has either 18 or 20 carbons (i.e., C18- or C20-sphingosine); we found that these 2 types of gangliosides are differentially distributed in the mouse brain. While the C18-species was widely distributed throughout the frontal brain, the C20-species selectively localized along the entorhinal-hippocampus projections, especially in the molecular layer (ML) of the dentate gyrus (DG). We revealed development- and aging-related accumulation of the C-20 species in the ML-DG. Thus it is possible to consider that this brain-region specific regulation of LCB chain length is particularly important for the distinct function in cells of CNS.
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Fast fingerprinting by MALDI-TOF mass spectrometry of urinary sediment glycosphingolipids in Fabry disease
Touboul, David; Roy, Sandrine; Germain, Dominique P.; Baillet, Arlette; Brion, Francoise; Prognon, Patrice; Chaminade, Pierre; Laprevote, Olivier
Analytical and Bioanalytical Chemistry (2005), 382 (5), 1209-1216CODEN: ABCNBP; ISSN:1618-2642. (Springer)
Fabry disease (FD) is an X-linked inborn error of glycosphingolipid (GSL) metab., caused by a deficiency of the lysosomal α-galactosidase A, which results in high levels in lysosomes and biol. fluids of globotriaosylceramide (Gb3) and digalactosylceramide (Ga2), also known as galabiosylceramide. The authors report here a detailed study of the mol. species of GSLs in urinary samples obtained from hemizygous and heterozygous patients by use of matrix-assisted laser desorption ionization and tandem mass spectrometry (MALDI-MS-MS). Twenty-two and fifteen mol. species were identified in the globotriaosylceramide and digalabiosylceramide series, resp. The major sphingoid base was sphingosine (d18:1), and dihydrosphingosine (C18:0) and sphingadienine (d18:2) were also present. The mol. profiles obtained by MALDI-TOF-MS enabled the authors to show significant differences between GSLs compn. for young, adult or atypic hemizygote and heterozygote patients. Thus, MALDI-TOF-MS and MS-MS proved a powerful tool for screening a population of patients with clin. signs suggestive of FD by direct and rapid GSL fingerprinting and identification, and for study of the biol. processes occurring in glycosphingolipid accumulation.
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Analysis of sphingolipids in potatoes (Solanum tuberosum L.) and sweet potatoes (Ipomoea batatas (L.) Lam.) by reversed phase high-performance liquid chromatography electrospray ionization tandem mass spectrometry (HPLC-ESI-MS/MS)
Bartke, Nana; Fischbeck, Anne; Humpf, Hans-Ulrich
Molecular Nutrition & Food Research (2006), 50 (12), 1201-1211CODEN: MNFRCV; ISSN:1613-4125. (Wiley-VCH Verlag GmbH & Co. KGaA)
Ceramides and glucocerebrosides of potatoes (Solanum tuberosum L.) and sweet potatoes (Ipomoea batatas (L.) Lam.) were analyzed using RP-HPLC-ESI-MS/MS. Ceramides and glucocerebrosides contg. the 3 different long-chain bases 4,8-sphingadienine (d18:2Δ4,Δ8), 4-hydroxy-8-sphingenine (t18:1Δ8), and 8-sphingenine (d18:1Δ8) acylated to satd. and unsatd. hydroxy- and nonhydroxy fatty acids with 16-26 C atoms were detected. For ceramides and glucocerebrosides 4,8-sphingadienine (d18:2Δ4,Δ8) was found as the major long-chain base, with lesser amts. of 4-hydroxy-8-sphingenine (t18:1Δ8) and 8-sphingenine (d18:1Δ8). 2-(α-)Hydroxypalmitic acid (C16:0h) was the major fatty acid, which was found to be acylated to the long-chain bases. For quantification of these compds., an RP-HPLC-ESI-MS/MS method with an "echo-peak"-technique simulating internal std. injection was developed. The analyzed samples of potatoes and sweet potatoes showed amts. of ∼0.1-8 μg/kg single ceramides and amts. up to 500 μg/kg glucocerebrosides, with C16:0h-glucosyl-4,8-sphingadienine as the major component.
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Umemura, Takeaki; Mori, Kenji
Agricultural and Biological Chemistry (1987), 51 (1), 217-24CODEN: ABCHA6; ISSN:0002-1369.
Stereoisomeric 2,3-erythro and 2,3-threo isomers of aplidiasphingosine (I) were synthesized in many steps from dithianeacetaldehyde (II). 13C NMR data confirmed their 2,3-threo and 13,14-erythro relative configurations.
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Obscuraminols, new unsaturated amino alcohols from the tunicate Pseudodistoma obscurum: structure and absolute configuration
Garrido, L.; Zubia, E.; Ortega, M. J.; Naranjo, S.; Salva, J.
Tetrahedron (2001), 57 (21), 4579-4588CODEN: TETRAB; ISSN:0040-4020. (Elsevier Science Ltd.)
The study of the ascidian Pseudodistoma obscurum from Tarifa Island (Cadiz, Spain) has led to the characterization of six new unsatd. 2-amino-3-ol compds., the obscuraminols A-F (e.g. I, obscuraminol A). Five of them, the obscuraminols B-F, were isolated as their corresponding diacetyl derivs. Their structures were established by spectroscopic anal., their relative configurations by NOEDS study of oxazolidinone derivs., and their abs. configurations by application of Mosher's method to N-acetyl derivs.
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Zhou, Bing-Nan; Mattern, Michael P.; Johnson, Randall K.; Kingston, David G. I.
Tetrahedron (2001), 57 (47), 9549-9554CODEN: TETRAB; ISSN:0040-4020. (Elsevier Science Ltd.)
Bioassay-directed fractionation of a sponge of the genus Calyx using a yeast bioassay for DNA-damaging agents yielded the novel sphingolipid calyxoside (I) as the major bioactive constituent. The structure of I was assigned as 1,3,26-trihydroxy-2,27-diaminooctacosan-18-one-1-β-D-glucoside by 1H- and 13C NMR, DEPT, DQCOSY, HMQC, and HMBC spectra. The carbonyl group was located at C-18 by anal. of the EI-MS fragmentation of the amino deriv. of its aglycon pentaacetate. Its abs. configuration was detd. as 2S,3R,26S,27S by anal. of the 1H NMR and CD spectra of its aglycon pentabenzoate.
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Cuadros, R.; de Garcini, E. M.; Wandosell, F.; Faircloth, G.; Fernandez-Sousa, J. M.; Avila, J. Cancer Lett. 2000, 152, 23
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The marine compound spisulosine, an inhibitor of cell proliferation, promotes the disassembly of actin stress fibers
Cuadros, R.; Montejo de Garcini, E.; Wandosell, F.; Faircloth, G.; Fernandez-Sousa, J. M.; Avila, J.
Cancer Letters (Shannon, Ireland) (2000), 152 (1), 23-29CODEN: CALEDQ; ISSN:0304-3835. (Elsevier Science Ireland Ltd.)
Spisulosine is a novel antiproliferative (antitumoral) compd. of marine origin. In this work the mol. target for this toxic agent has been analyzed. In the presence of spisulosine, cultured cells change their morphol., first acquiring a fusiform morphol., and later becoming rounded without focal adhesions. Anal. of the cytoskeleton of treated cells indicate the absence of actin stress fibers.
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Gelderblom, W. C.; Jaskiewicz, K.; Marasas, W. F.; Thiel, P. G.; Horak, R. M.; Vleggaar, R.; Kriek, N. P. Appl. Environ. Microbiol. 1988, 54, 1806
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Fumonisins-novel mycotoxins with cancer-promoting activity produced by Fusarium moniliforme
Gelderblom, W. C. A.; Jaskiewicz, K.; Marasas, W. F. O.; Thiel, P. G.; Horak, R. M.; Vleggaar, R.; Kriek, N. P. J.
Applied and Environmental Microbiology (1988), 54 (7), 1806-11CODEN: AEMIDF; ISSN:0099-2240.
Culture material of F. moniliforme isolate exhibits cancer-promoting activity in a short-term cancer initiation-promotion bioassay with diethylnitrosamine-initiated rats and induces γ-glutamyltranspeptidase-pos. (GGT+) foci as an endpoint after 4 wk of promotion. This bioassay was used as a monitoring system to isolate cancer-promoting compds. from cultures of F. moniliforme MRC 826. Culture material was successively extd. with Et acetate and MeOH-H2O (3:1). Most of the cancer-promoting activity was recovered in the MeOH-H2O ext. and remained in the aq. phase following partitioning of this ext. between MeOH-H2O (1:3) and CHCl3. The MeOH-H2O fraction was chromatographed on an Amberlite XAD-2 column, and the active fraction was eluted with MeOH. This fraction was chromatographed on a silica gel column with CHCl3-MeOH-MeCO2H (6:3:1) as eluent and further purified on a C18 reverse-phase column. Two pure compds. were isolated, and these have been chem. characterized and given the trivial names fumonisin B1 and B2. At least 2 g of the major compd. fumonisin B1 was purified from 1 kg of culture material. Fumonisin B1 in the diet (0.1%) significantly induced the formation of GGT+ foci in the livers of initiated as well as noninitiated rats. The cancer-promoting effect of fumonisin B1 in rats was assocd. with a toxic effect, as evidenced by a significant redn. in wt. gain during the 4-wk promoting treatment. The principal pathol. change in rats treated with fumonisin B1 was an insidious and progressive toxic hepatitis similar to that induced by toxic culture material of F. moniliforme MRC 826.
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Wang, E.; Norred, W. P.; Bacon, C. W.; Riley, R. T.; Merrill, A. H., Jr. J. Biol. Chem. 1991, 266, 14486
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Inhibition of sphingolipid biosynthesis by fumonisins. Implications for diseases associated with Fusarium moniliforme
Wang, Elaine; Norred, William P.; Bacon, Charles W.; Riley, Ronald T.; Merrill, Alfred H., Jr.
Journal of Biological Chemistry (1991), 266 (22), 14486-90CODEN: JBCHA3; ISSN:0021-9258.
Incubation of rat hepatocytes with fumonisins inhibited incorporation of [14C]serine into the sphingosine moiety of cellular sphingolipids with an IC50 of 0.1 μM for fumonisin B1 (I). In contrast, I increased the amt. of the biosynthetic intermediate sphinganine, which suggests that fumonisins inhibit the conversion of [14C]sphinganine to N-acyl-[14C]sphinganines, a step that is thought to precede introduction of the 4,5-trans double bond of sphingosine (1986). In agreement with this mechanism, I inhibited the activity of sphingosine N-acyltransferase (ceramide synthase) in rat liver microsomes with 50% inhibition at approx. 0.1 μM and reduced the conversion of [3H]sphingosine to [3H]ceramide by intact hepatocytes. As far as the authors are aware, this is the 1st discovery of a naturally occurring inhibitor of this step of sphingolipid metab. These findings suggest that disruption of the de novo pathway of sphingolipid biosynthesis may be a crit. event in the diseases that have been assocd. with consumption of fumonisins.
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Marasas, W. F.; Riley, R. T.; Hendricks, K. A.; Stevens, V. L.; Sadler, T. W.; Gelineau-van Waes, J.; Missmer, S. A.; Cabrera, J.; Torres, O.; Gelderblom, W. C.; Allegood, J.; Martinez, C.; Maddox, J.; Miller, J. D.; Starr, L.; Sullards, M. C.; Roman, A. V.; Voss, K. A.; Wang, E.; Merrill, A. H., Jr. J. Nutr. 2004, 134, 711
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Fumonisins disrupt sphingolipid metabolism, folate transport, and neural tube development in embryo culture and in vivo: a potential risk factor for human neural tube defects among populations consuming fumonisin-contaminated maize
Marasas, Walter F. O.; Riley, Ronald T.; Hendricks, Katherine A.; Stevens, Victoria L.; Sadler, Thomas W.; Gelineau-van Waes, Janee; Missmer, Stacey A.; Cabrera, Julio; Torres, Olga; Gelderblom, Wentzel C. A.; Allegood, Jeremy; Martinez, Carolina; Maddox, Joyce; Miller, J. David; Starr, Lois; Sullards, M. Cameron; Roman, Ana Victoria; Voss, Kenneth A.; Wang, Elaine; Merrill, Alfred H., Jr.
Journal of Nutrition (2004), 134 (4), 711-716CODEN: JONUAI; ISSN:0022-3166. (American Society for Nutritional Sciences)
A review. Fumonisins are a family of toxic and carcinogenic mycotoxins produced by Fusarium verticillioides (formerly Fusarium moniliforme), a common fungal contaminant of maize. Fumonisins inhibit ceramide synthase, causing accumulation of bioactive intermediates of sphingolipid metab. (sphinganine and other sphingoid bases and derivs.) as well as depletion of complex sphingolipids, which interferes with the function of some membrane proteins, including the folate-binding protein (human folate receptor α). Fumonisin causes neural tube and craniofacial defects in mouse embryos in culture. Many of these effects are prevented by supplemental folic acid. Recent studies in LMBc mice found that fumonisin exposure in utero increases the frequency of developmental defects and administration of folate or a complex sphingolipid is preventive. High incidences of neural tube defects (NTD) occur in some regions of the world where substantial consumption of fumonisins has been documented or plausibly suggested (Guatemala, South Africa, and China); furthermore, a recent study of NTD in border counties of Texas found a significant assocn. between NTD and consumption of tortillas during the first trimester. Hence, the authors propose that fumonisins are potential risk factors for NTD, craniofacial anomalies, and other birth defects arising from neural crest cells because of their apparent interference with folate utilization.
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Merrill, A. H., Jr.; Liotta, D. C.; Riley, R. T. Trends Cell Biol. 1996, 6, 218
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Fumonisins: Fungal toxins that shed light on sphingolipid function
Merrill, Alfred H. Jr.; Liotta, Dennis C.; Riley, Ronald T.
Trends in Cell Biology (1996), 6 (6), 218-223CODEN: TCBIEK; ISSN:0962-8924. (Elsevier Trends Journals)
A review and discussion with 52 refs. Fumonisins are sphinganine analogs produced by Fusarium moniliforme and related fungi. They inhibit ceramide synthase and block the biosynthesis of complex sphingolipids, promoting accumulation of sphinganine and sphinganine 1-phosphate. Disruption of sphingolipid metab. by fumonisin B1 alters cell-cell interactions, the behavior of cell-surface proteins, the activity of protein kinases, the metab. of other lipids, and cell growth and viability. This multitude of effects probably accounts for the toxicity and carcinogenicity of these mycotoxins. Naturally occurring inhibitors of sphingolipid metab. such as fumonisins are proving to be powerful tools for studying the diverse roles of sphingolipids in cell regulation and disease.
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Miyake, Y.; Kozutsumi, Y.; Nakamura, S.; Fujita, T.; Kawasaki, T. Biochem. Biophys. Res. Commun. 1995, 211, 396
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Hanada, K.; Nishijima, M.; Fujita, T.; Kobayashi, S. Biochem. Pharmacol. 2000, 59, 1211
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Ikushiro, H.; Hayashi, H.; Kagamiyama, H. Biochemistry 2004, 43, 1082
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Fujita, T.; Hirose, R.; Yoneta, M.; Sasaki, S.; Inoue, K.; Kiuchi, M.; Hirase, S.; Chiba, K.; Sakamoto, H.; Arita, M. J. Med. Chem. 1996, 39, 4451
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Thangada, S; Khanna, K. M.; Blaho, V. A.; Oo, M. L.; Im, D. S.; Guo, C; Lefrancois, L; Hla, T. J Exp. Med. 2010, 207, 1475
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Pyne, S.; Pyne, N. J. Trends Mol. Med. 2011, 17, 463
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Ter Braak, M.; Claas, R. F.; Hegen, B.; Labocha, S.; Ferreiros, N.; Pfeilschifter, J.; Huwiler, A.; van Echten-Deckert, G.; Meyer Zu Heringdorf, D. Biochem. Pharmacol. 2011, 81, 617
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van Echten-Deckert, G.; Zschoche, A.; Bar, T.; Schmidt, R. R.; Raths, A.; Heinemann, T.; Sandhoff, K. J. Biol. Chem. 1997, 272, 15825
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Schwartz, G. K.; Ward, D.; Saltz, L.; Casper, E. S.; Spiess, T.; Mullen, E.; Woodworth, J.; Venuti, R.; Zervos, P.; Storniolo, A. M.; Kelsen, D. P. Clin. Cancer Res. 1997, 3, 537
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A pilot clinical/pharmacological study of the protein kinase C-specific inhibitor safingol alone and in combination with doxorubicin
Schwartz, Gary K.; Ward, David; Saltz, Leonard; Casper, Ephraim S.; Spiess, Tara; Mullen, Eillen; Woodworth, Jim; Venuti, Robert; Zervos, Peter; et al.
Clinical Cancer Research (1997), 3 (4), 537-543CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)
We performed a pilot clin. trial with safingol (L-threo-dihydrosphingosine), a protein kinase C-specific inhibitor that potentiates the effect of doxorubicin (DOX) in tumor-bearing animals. Safingol was initially administered as a 1-h infusion at escalating doses. Fourteen days later, patients received the same dose of safingol in combination with a fixed dose of DOX. The combination was repeated at 3-wk intervals. Safingol dose levels ranged from 15 to 120 mg/m2. The plasma levels achieved at the final dose level were comparable to those assocd. with potentiation of DOX in animals. The mean Cmax and area under the curve for safingol at the 120 mg/m2 dose level were 1040 ± 196 ng/mL and 1251 ± 317 mg × h/mL, resp. The mean plasma half-life for safingol was 3.97 ± 2.51 h, the mean estd. clearance was 3140 ± 765 mL/min, and the mean vol. of distribution was of 995 ± 421 L. Coadministration of a fixed dose of DOX did not significantly change the pharmacokinetics of safingol, nor did increasing doses of safingol significantly affect the pharmacokinetics of DOX. Minor responses were obsd. in three patients with pancreatic cancer and one patient with angiosarcoma of the scalp. This pilot Phase I study indicates that the protein kinase C inhibitor safingol can be given safely with 45 mg/m2 of DOX at a dose that is potentially pharmacol. active without dose-limiting toxicity.
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Coward, J.; Ambrosini, G.; Musi, E.; Truman, J. P.; Haimovitz-Friedman, A.; Allegood, J. C.; Wang, E.; Merrill, A. H., Jr.; Schwartz, G. K. Autophagy 2009, 5, 184
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Dickson, M. A.; Carvajal, R. D.; Merrill, A. H., Jr.; Gonen, M.; Cane, L. M.; Schwartz, G. K. Clin. Cancer Res. 2011, 17, 2484
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A Phase I Clinical Trial of Safingol in Combination with Cisplatin in Advanced Solid Tumors
Dickson, Mark A.; Carvajal, Richard D.; Merrill, Alfred H., Jr.; Gonen, Mithat; Cane, Lauren M.; Schwartz, Gary K.
Clinical Cancer Research (2011), 17 (8), 2484-2492CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)
Sphingosine 1-phosphate (S1P) is an important mediator of cancer cell growth and proliferation. Prodn. of S1P is catalyzed by sphingosine kinase 1 (SphK). Safingol, (L-threo-dihydrosphingosine) is a putative inhibitor of SphK. We conducted a phase I trial of safingol (S) alone and in combination with cisplatin (C). A 3 + 3 dose escalation was used. For safety, S was given alone 1 wk before the combination. S + C were then administered every 3 wk. S was given over 60 to 120 min, depending on dose. Sixty minutes later, C was given over 60 min. The C dose of 75 mg/m2 was reduced in cohort 4 to 60 mg/m2 due to excessive fatigue. Forty-three patients were treated, 41 were evaluable for toxicity, and 37 for response. The max. tolerated dose (MTD) was S 840 mg/m2 over 120 min C 60 mg/m2, every 3 wk. Dose-limiting toxicity (DLT) attributed to cisplatin included fatigue and hyponatremia. DLT from S was hepatic enzyme elevation. S pharmacokinetic parameters were linear throughout the dose range with no significant interaction with C. Patients treated at or near the MTD achieved S levels of more than 20 μmol/L and maintained levels greater than and equal to 5 μmol/L for 4 h. The best response was stable disease in 6 patients for on av. 3.3 mo (range 1.8-7.2 m). One patient with adrenal cortical cancer had significant regression of liver and lung metastases and another had prolonged stable disease. S was assocd. with a dose-dependent redn. in S1P in plasma. Safingol, the first putative SphK inhibitor to enter clin. trials, can be safely administered in combination with cisplatin. Reversible dose-dependent hepatic toxicity was seen, as expected from preclin. data. Target inhibition was achieved with downregulation of S1P. The recommended phase II dose is S 840 mg/m2 and C 60 mg/m2, every 3 wk. Clin Cancer Res; 17(8); 2484-92.
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Symolon, H.; Bushnev, A.; Peng, Q.; Ramaraju, H.; Mays, S. G.; Allegood, J. C.; Pruett, S. T.; Sullards, M. C.; Dillehay, D. L.; Liotta, D. C.; Merrill, A. H., Jr. Mol. Cancer Ther. 2011, 10, 648
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Enigmol: A Novel Sphingolipid Analogue with Anticancer Activity against Cancer Cell Lines and In vivo Models for Intestinal and Prostate Cancer
Symolon, Holly; Bushnev, Anatoliy; Peng, Qiong; Ramaraju, Harsha; Mays, Suzanne G.; Allegood, Jeremy C.; Pruett, Sarah T.; Sullards, M. Cameron; Dillehay, Dirck L.; Liotta, Dennis C.; Merrill, Alfred H., Jr.
Molecular Cancer Therapeutics (2011), 10 (4), 648-657CODEN: MCTOCF; ISSN:1535-7163. (American Association for Cancer Research)
Sphingoid bases are cytotoxic for many cancer cell lines and are thought to contribute to suppression of intestinal tumorigenesis in vivo by ingested sphingolipids. This study explored the behavior of a sphingoid base analog, (2S,3S,5S)-2-amino-3,5-dihydroxyoctadecane (Enigmol), that cannot be phosphorylated by sphingosine kinases and is slowly N-acylated and therefore is more persistent than natural sphingoid bases. Enigmol had potential anticancer activity in a National Cancer Institute (NCI-60) cell line screen and was confirmed to be more cytotoxic and persistent than naturally occurring sphingoid bases using HT29 cells, a colon cancer cell line. Although the mol. targets of sphingoid bases are not well delineated, Enigmol shared one of the mechanisms that has been found for naturally occurring sphingoid bases: normalization of the aberrant accumulation of β-catenin in the nucleus and cytoplasm of colon cancer cells due to defect(s) in the adenomatous polyposis coli (APC)/β-catenin regulatory system. Enigmol also had antitumor efficacy when administered orally to Min mice, a mouse model with a truncated APC gene product (C57Bl/6JMin/+ mice), decreasing the no. of intestinal tumors by half at 0.025% of the diet (wt./wt.), with no evidence of host toxicity until higher dosages. Enigmol was also tested against the prostate cancer cell lines DU145 and PC-3 in nude mouse xenografts and suppressed tumor growth in both. Thus, Enigmol represents a novel category of sphingoid base analog that is orally bioavailable and has the potential to be effective against multiple types of cancer. Mol Cancer Ther; 10(4); 648-57.
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Baird, R. D.; Kitzen, J.; Clarke, P. A.; Planting, A.; Reade, S.; Reid, A.; Welsh, L.; Lopez Lazaro, L.; de las Heras, B.; Judson, I. R.; Kaye, S. B.; Eskens, F.; Workman, P.; deBono, J. S.; Verweij, J. Mol. Cancer Ther. 2009, 8, 1430
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Phase I safety, pharmacokinetic, and pharmacogenomic trial of ES-285, a novel marine cytotoxic agent, administered to adult patients with advanced solid tumors
Baird, Richard D.; Kitzen, Jos; Clarke, Paul A.; Planting, Andre; Reade, Sarah; Reid, Alison; Welsh, Lyndsey; Lopez Lazaro, Luis; de las Heras, Begona; Judson, Ian R.; Kaye, Stan B.; Eskens, Ferry; Workman, Paul; de Bono, Johann S.; Verweij, Jaap
Molecular Cancer Therapeutics (2009), 8 (6), 1430-1437CODEN: MCTOCF; ISSN:1535-7163. (American Association for Cancer Research)
A dose-escalation, phase I study evaluated the safety, pharmacokinetics, pharmacogenomics, and efficacy of ES-285, a novel agent isolated from a marine mollusc, in adult cancer patients. Patients received a 24-h i.v. infusion of ES-285 once every 3 wk until disease progression or unacceptable toxicity. The starting dose was 4 mg/m2. Dose escalation in cohorts of at least three patients proceeded according to the worst toxicity obsd. in the previous cohort. Twenty-eight patients were treated with 72 courses of ES-285 across eight dose levels. No dose-limiting toxicities were seen between 4 and 128 mg/m2. Two of four patients treated at 256 mg/m2 had dose-limiting reversible grade 3 transaminitis; one patient at 256 mg/m2 also had transient grade 3 central neurotoxicity. One of three patients subsequently treated at 200 mg/m2 died following drug-related central neurotoxicity. Other toxicities included phlebitis, nausea, fatigue, and fever. Pharmacokinetic studies indicated dose proportionality with high vol. of distribution (median Vss at 256 mg/m2 was 2,389 L; range, 1,615-4,051 L) and long elimination half life (median t1/2 at 256 mg/m2 was 28 h; range, 21-32 h). The three patients with dose-limiting toxicity had the highest drug exposure. Pharmacogenomic studies of paired surrogate tissue samples identified changes in gene expression following treatment that correlated with increasing dose. Disease stabilization for 6 to 18 wk was recorded in nine patients. Using this schedule, 128 mg/m2 was considered safe and feasible. At this dose, pharmacol. relevant concns. of the drug were safely achieved with pharmacogenomic studies indicating changes in the expression of genes of potential mechanistic relevance.
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Schoffski, P.; Dumez, H.; Ruijter, R.; Miguel-Lillo, B.; Soto-Matos, A.; Alfaro, V.; Giaccone, G. Cancer Chemother. Pharmacol. 2011, DOI: 10.1007/s00280-011-1612-1
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Faircloth, G.; Cuevas, C. Prog. Mol. Subcell. Biol. 2006, 43, 363
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Kahalalide F and ES285: potent anticancer agents from marine molluscs
Faircloth, G.; Cuevas, C.
Progress in Molecular and Subcellular Biology (2006), 43 (Molluscs), 363-379CODEN: PMSBA4; ISSN:0079-6484. (Springer-Verlag)
A review. The marine environment is proving to be a very rich source of unique compds. with significant activities against cancer of several types. Finding the sources of these new chem. entities has made it necessary for marine and medical scientists to find enterprising ways to collaborate in order to sample the great variety of intertidal, shallow and deep-water sea life. Recently these efforts resulted in a first generation of drugs from the sea undergoing clin. trials. These include PharmaMar compds.: Yondelis, Aplidin, kahalalide F, ES285 and Zalypsis. Two of these compds., kahalalide F and ES285, have been isolated from the Indopacific mollusc Elysia rufescens and the North Atlantic mollusc Spisula polynyma, resp.
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Menaldino, D. S.; Bushnev, A.; Sun, A.; Liotta, D. C.; Symolon, H.; Desai, K.; Dillehay, D. L.; Peng, Q.; Wang, E.; Allegood, J.; Trotman-Pruett, S.; Sullards, M. C.; Merrill, A. H., Jr. Pharmacol. Res. 2003, 47, 373
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Sphingoid bases and de novo ceramide synthesis: enzymes involved, pharmacology and mechanisms of action
Menaldino, David S.; Bushnev, Anatoliy; Sun, Aiming; Liotta, Dennis C.; Symolon, Holly; Desai, Kena; Dillehay, Dirck L.; Peng, Qiong; Wang, Elaine; Allegood, Jeremy; Trotman-Pruett, Sarah; Sullards, M. Cameron; Merrill, Alfred H.
Pharmacological Research (2003), 47 (5), 373-381CODEN: PHMREP; ISSN:1043-6618. (Elsevier Science Ltd.)
A review. The sphingoid base backbones of sphingolipids (sphingosines, sphinganines, 4-hydroxysphinganines and others) are highly bioactive species directly and-in most cases-as their metabolites, the N-acyl-sphingoid bases (ceramides) and sphingoid base 1-phosphates. The complexity of these compds. affords many opportunities to prep. synthetic analogs for studies of sphingolipid metab. and the functions of the sphingoid bases and metabolites. Described in this review are methods for the prepn. of libraries of sphingoid bases, including a series of 1-deoxy-analogs, as well as information about their metab. and biol. activities. Findings with these compds. have uncovered some of the complications of working with compds. that mimic a naturally occurring biomodulator-such as that they are sometimes metabolized by enzymes that handle the endogenous compds. and the products may have potent (and unexpected) biol. activities. Through studying such compds., there is now a greater understanding of the metab. and mechanism(s) of action of naturally occurring sphingoid bases as well as of these analogs.
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Zheng, W.; Kollmeyer, J.; Symolon, H.; Momin, A.; Munter, E.; Wang, E.; Kelly, S.; Allegood, J. C.; Liu, Y.; Peng, Q.; Ramaraju, H.; Sullards, M. C.; Cabot, M.; Merrill, A. H., Jr. Biochim. Biophys. Acta 2006, 1758, 1864
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Fyrst, H.; Oskouian, B.; Bandhuvula, P.; Gong, Y.; Byun, H. S.; Bittman, R.; Lee, A. R.; Saba, J. D. Cancer Res. 2009, 69, 9457
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Liu, K.; Zhang, X.; Sumanasekera, C.; Lester, R. L.; Dickson, R. C. Biochem. Soc. Trans. 2005, 33, 1170
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Signalling functions for sphingolipid long-chain bases in Saccharomyces cerevisiae
Liu, K.; Zhang, X.; Sumanasekera, C.; Lester, R. L.; Dickson, R. C.
Biochemical Society Transactions (2005), 33 (5), 1170-1173CODEN: BCSTB5; ISSN:0300-5127. (Portland Press Ltd.)
Over the past several years, studies of sphingolipid functions in the baker's yeast Saccharomyces cerevisiae have revealed that the sphingid LCBs (long-chain bases), dihydrosphingosine and PHS (phytosphingosine), are important signaling mols. or second messengers under heat stress and during non-stressed conditions. LCBs are now recognized as regulators of AGC-type protein kinase (where AGC stands for protein kinases A, G and C) Pkh1 and Pkh2, which are homologues of mammalian phosphoinositide-dependent protein kinase 1. LCBs were previously shown to activate Pkh1 and Pkh2, which then activate the downstream protein kinase Pkc1. The authors have demonstrated that PHS stimulates Pkh1 to activate addnl. downstream kinases including Ypk1, Ypk2 and Sch9. They have also found that PHS acts downstream of Pkh1 and partially activates Ypk1, Ypk2 and Sch9. These kinases control a wide range of cellular processes including growth, cell wall integrity, stress resistance, endocytosis and aging. As we learn more about the cellular processes controlled by Ypk1, Ypk2 and Sch9, we will have a far greater appreciation of LCBs as second messengers.
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Wertz, P. W. Acta Derm. Venereol. Suppl. (Stockh.) 2000, 208, 7
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Lipids and barrier function of the skin
Wertz P W
Acta dermato-venereologica. Supplementum (2000), 208 (), 7-11 ISSN:0365-8341.
The purpose of the present manuscript is to review the chemical and physical properties of epidermal lipids and to relate these properties to the formation and function of the permeability barrier of the skin. Lipids accumulate in small organelles known as lamellar granules as epidermal keratinocytes differentiate. This lipid is extruded into the intercellular spaces where it undergoes enzymatic processing to produce a lipid mixture consisting of ceramides, cholesterol and fatty acids. This intercellular lipid is uniquely organized into a multilamellar complex that fills most of the intercellular space of the stratum corneum. The barrier properties of the stratum corneum are related to the phase behavior of the intercellular lipids. It has been proposed that a structurally unusual acylglucosylceramide is thought to be involved in assembly of the lamellar granules, and a related acylceramide may have a major influence on the organization of the lamellae in the stratum corneum.
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Wartewig, S.; Neubert, R. H. Skin Pharmacol. Physiol. 2007, 20, 220
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Properties of ceramides and their impact on the stratum corneum structure
Wartewig, S.; Neubert, R. H. H.
Skin Pharmacology and Physiology (2007), 20 (5), 220-229CODEN: SPPKE6; ISSN:1660-5527. (S. Karger AG)
A review. The lipid matrix of the stratum corneum (SC) is the major diffusion-rate-limiting pathway by which most drugs intracellularly pass the SC. The major lipid classes extd. from the SC are ceramides, cholesterol, and free fatty acids. Ceramides that comprise 9 subclasses play a crucial role in maintaining the barrier function of the skin. A profound knowledge of the phys. properties of ceramides is essential for a deeper understanding of the impact of each ceramide species on the barrier function. Here, the authors summarize the thermotropic and/or lyotropic behavior of sphingosine-type ceramides (CER AS, CER NS) and phytosphingosine-type ceramides (CER AP, CER NP) revealed by DSC, x-ray diffraction, FTIR spectroscopy, and FT-Raman spectroscopy in past decades. Polymorphism is a characteristic feature of ceramides. At physiol. temps., all cryst. phases of ceramides exhibit lamellar structures with highly ordered hydrocarbon chains. The differential behavior of the head groups of ceramides may be an important determinant for the skin barrier function.
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The role of epidermal lipids in cutaneous permeability barrier homeostasis
Feingold, Kenneth R.
Journal of Lipid Research (2007), 48 (12), 2531-2546CODEN: JLPRAW; ISSN:0022-2275. (American Society for Biochemistry and Molecular Biology, Inc.)
A review. The permeability barrier is required for terrestrial life and is localized to the stratum corneum, where extracellular lipid membranes inhibit water movement. The lipids that constitute the extracellular matrix have a unique compn. and are 50% ceramides, 25% cholesterol, and 15% free fatty acids. Essential fatty acid deficiency results in abnormalities in stratum corneum structure function. The lipids are delivered to the extracellular space by the secretion of lamellar bodies, which contain phospholipids, glucosylceramides, sphingomyelin, cholesterol, and enzymes. In the extracellular space, the lamellar body lipids are metabolized by enzymes to the lipids that form the lamellar membranes. The lipids contained in the lamellar bodies are derived from both epidermal lipid synthesis and extracutaneous sources. Inhibition of cholesterol, fatty acid, ceramide, or glucosylceramide synthesis adversely affects lamellar body formation, thereby impairing barrier homeostasis. Studies have further shown that the elongation and desatn. of fatty acids is also required for barrier homeostasis. The mechanisms that mediate the uptake of extracutaneous lipids by the epidermis are unknown, but keratinocytes express LDL and scavenger receptor class B type 1, fatty acid transport proteins, and CD36. Topical application of physiol. lipids can improve permeability barrier homeostasis and has been useful in the treatment of cutaneous disorders.
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Walden, C. M.; Sandhoff, R.; Chuang, C. C.; Yildiz, Y.; Butters, T. D.; Dwek, R. A.; Platt, F. M.; van der Spoel, A. C. J. Biol. Chem. 2007, 282, 32655
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Rabionet, M.; van der Spoel, A. C.; Chuang, C. C.; von Tumpling-Radosta, B.; Litjens, M.; Bouwmeester, D.; Hellbusch, C. C.; Korner, C.; Wiegandt, H.; Gorgas, K.; Platt, F. M.; Grone, H. J.; Sandhoff, R. J. Biol. Chem. 2008, 283, 13357
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Van Overloop, H.; Denizot, Y.; Baes, M.; Van Veldhoven, P. P. Biol. Chem. 2007, 388, 315
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Bielawska, A.; Linardic, C. M.; Hannun, Y. A. FEBS Lett. 1992, 307, 211
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Bielawska, A.; Crane, H. M.; Liotta, D.; Obeid, L. M.; Hannun, Y. A. J. Biol. Chem. 1993, 268, 26226
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Bielawska, A.; Greenberg, M. S.; Perry, D.; Jayadev, S.; Shayman, J. A.; McKay, C.; Hannun, Y. A. J. Biol. Chem. 1996, 271, 12646
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van Echten-Deckert, G.; Giannis, A.; Schwarz, A.; Futerman, A. H.; Sandhoff, K. J. Biol. Chem. 1998, 273, 1184
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Senkal, C. E.; Ponnusamy, S.; Rossi, M. J.; Sundararaj, K.; Szulc, Z.; Bielawski, J.; Bielawska, A.; Meyer, M.; Cobanoglu, B.; Koybasi, S.; Sinha, D.; Day, T. A.; Obeid, L. M.; Hannun, Y. A.; Ogretmen, B. J. Pharmacol. Exp. Ther. 2006, 317, 1188
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Potent antitumor activity of a novel cationic pyridinium-ceramide alone or in combination with gemcitabine against human head and neck squamous cell carcinomas in vitro and in vivo
Senkal, Can E.; Ponnusamy, Suriyan; Rossi, Michael J.; Sundararaj, Kamala; Szulc, Zdzislaw; Bielawski, Jacek; Bielawska, Alicja; Meyer, Mario; Cobanoglu, Bengu; Koybasi, Serap; Sinha, Debajyoti; Day, Terry A.; Obeid, Lina M.; Hannun, Yusuf A.; Ogretmen, Besim
Journal of Pharmacology and Experimental Therapeutics (2006), 317 (3), 1188-1199CODEN: JPETAB; ISSN:0022-3565. (American Society for Pharmacology and Experimental Therapeutics)
In this study, a cationic water-sol. ceramide analog L-threo-C6-pyridinium-ceramide-bromide (L-t-C6-Pyr-Cer), which exhibits high soly. and bioavailability, inhibited the growth of various human head and neck squamous cell carcinoma (HNSCC) cell lines at low IC50 concns., independent of their p53 status. Consistent with its design to target neg. charged intracellular compartments, L-t-C6-Pyr-Cer accumulated mainly in mitochondria-, and nuclei-enriched fractions upon treatment of human UM-SCC-22A cells [human squamous cell carcinoma (SCC) of the hypopharynx] at 1 to 6 h. In addn. to its growth-inhibitory function as a single agent, the supra-additive interaction of L-t-C6-Pyr-Cer with gemcitabine (GMZ), a chemotherapeutic agent used in HNSCC, was detd. using isobologram studies. Then, the effects of this ceramide, alone or in combination with GMZ, on the growth of UM-SCC-22A xenografts in SCID mice was assessed following the detn. of preclin. parameters, such as max. tolerated dose, clearance from the blood, and bioaccumulation. Results demonstrated that treatment with L-t-C6-Pyr-Cer in combination with GMZ significantly prevented the growth of HNSCC tumors in vivo. The therapeutic efficacy of L-t-C6-Pyr-Cer/GMZ combination against HNSCC tumors was approx. 2.5-fold better than that of the combination of 5-fluorouracil/cisplatin. In addn., liq. chromatog./mass spectroscopy anal. showed that the levels of L-t-C6-Pyr-Cer in HNSCC tumors were significantly higher than its levels in the liver and intestines; interestingly, the combination with GMZ increased the sustained accumulation of this ceramide by approx. 40%. Moreover, treatment with L-t-C6-Pyr-Cer/GMZ combination resulted in a significant inhibition of telomerase activity and decrease in telomere length in vivo, which are among downstream targets of ceramide.
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Struckhoff, A. P.; Bittman, R.; Burow, M. E.; Clejan, S.; Elliott, S.; Hammond, T.; Tang, Y.; Beckman, B. S. J. Pharmacol. Exp. Ther. 2004, 309, 523
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112
Novel ceramide analogs as potential chemotherapeutic agents in breast cancer
Struckhoff, Amanda P.; Bittman, Robert; Burow, Matthew E.; Clejan, Sanda; Elliott, Steven; Hammond, Timothy; Tang, Yan; Beckman, Barbara S.
Journal of Pharmacology and Experimental Therapeutics (2004), 309 (2), 523-532CODEN: JPETAB; ISSN:0022-3565. (American Society for Pharmacology and Experimental Therapeutics)
Recent evidence suggests a role for aberrant ceramide levels in the pathogenesis of cancer and chemoresistance and indicates that manipulation of tumor ceramide levels may be a useful strategy in the fight against breast cancer. This study demonstrates that alterations in the degree and position of unsatn. of bonds in the sphingoid backbone of D-erythro-N-octanoyl-sphingosine (Cer) affect the antiproliferative ability of ceramide analogs in breast cancer cells. The most potent analog of Cer we tested is (2S,3R)-(4E,6E)-2-octanoylamidoocta- decadiene-1,3-diol (4,6-diene-Cer), which contains an addnl. trans double bond at C(6)-C(7) of the sphingoid backbone. 4,6-Diene-Cer exhibited higher potency than Cer in tumor necrosis factor (TNF)-α-resistant (IC50 of 11.3 vs. 32.9 μM) and TNF-α-sensitive (IC50 of 13.7 vs. 37.7 μM) MCF-7 cells. 4,6-Diene-Cer was also more potent than Cer in inducing cell death in MDA-MB-231 and NCI/ADR-RES breast cancer cell lines (IC50 of 3.7 vs. 11.3 μM, and 24.1 vs. 86.9 μM, resp.). 4,6-Diene-Cer caused a prolonged elevation of intracellular ceramide levels in MCF-7 cells, which may contribute to its enhanced cytotoxicity. Furthermore, treatment of MCF-7 cells with Cer or 4,6-diene-Cer resulted in induction of apoptosis by 8 h via the mitochondrial pathway, as demonstrated by release of cytochrome c, loss of membrane asymmetry (measured by Annexin V staining), and a decrease in the mitochondrial membrane potential. Importantly, both Cer and 4,6-diene-Cer displayed selectivity toward transformed breast cells over nontransformed breast epithelial cells. These data suggest that these and other novel ceramide analogs represent potential therapeutic agents in breast cancer treatment.
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Bittman, R.; Li, Z.; Samadder, P.; Arthur, G. Cancer Lett. 2007, 251, 53
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Anticancer activity of a ceramide analog containing a disulfide linkage
Bittman, Robert; Li, Zaiguo; Samadder, Pranati; Arthur, Gilbert
Cancer Letters (Amsterdam, Netherlands) (2007), 251 (1), 53-58CODEN: CALEDQ; ISSN:0304-3835. (Elsevier B.V.)
The effects of exogenous short-chain ceramide (1) on the arrest of growth of cancer cells in vitro and induction of apoptosis have been well documented. In the present study, an analog of 1 with a disulfide linkage, N-(4',5'-dithiaheptanoyl)-D-erythro-ceramide (2), was synthesized and found to be significantly more antiproliferative and cytotoxic than 1 in BT549, A549, and DU145 cancer cells. The activity was correlated with a redn. in cellular glutathione (GSH) level. Ceramide analogs with a tri- and tetra-sulfide moiety were also prepd., but they did not deplete cellular GSH levels and did not possess antiproliferative or cytotoxic properties.
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Stover, T. C.; Kim, Y. S.; Lowe, T. L.; Kester, M. Biomaterials 2008, 29, 359
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115
Liu, X.; Ryland, L.; Yang, J.; Liao, A.; Aliaga, C.; Watts, R.; Tan, S. F.; Kaiser, J.; Shanmugavelandy, S. S.; Rogers, A.; Loughran, K.; Petersen, B.; Yuen, J.; Meng, F.; Baab, K. T.; Jarbadan, N. R.; Broeg, K.; Zhang, R.; Liao, J.; Sayers, T. J.; Kester, M.; Loughran, T. P., Jr. Blood 2010, 116, 4192
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116
Tagaram, H. R.; Divittore, N. A.; Barth, B. M.; Kaiser, J. M.; Avella, D.; Kimchi, E. T.; Jiang, Y.; Isom, H. C.; Kester, M.; Staveley-O’Carroll, K. F. Gut 2011, 60, 695
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Megha; Sawatzki, P.; Kolter, T.; Bittman, R.; London, E. Biochim. Biophys. Acta 2007, 1768, 2205
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Goni, F. M.; Contreras, F. X.; Montes, L. R.; Sot, J.; Alonso, A. Biochem. Soc. Symp. 2005, 177
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Biophysics (and sociology) of ceramides
Goni, Felix M.; Contreras, F.-Xabier; Montes, L.-Ruth; Sot, Jesus; Alonso, Alicia
Biochemical Society Symposia (2005), 72 (Lipids, Rafts and Traffic), 177-188CODEN: BSSYAT; ISSN:0067-8694. (Portland Press Ltd.)
A review. In the past decade, the long-neglected ceramides (N-acylsphingosines) have become one of the most attractive lipid mols. in mol. cell biol., because of their involvement in essential structures (stratum corneum) and processes (cell signalling). Most natural ceramides have a long (16-24 C atoms) N-acyl chain, but short N-acyl chain ceramides (two to six C atoms) also exist in Nature, apart from being extensively used in experimentation, because they can be dispersed easily in water. Long-chain ceramides are among the most hydrophobic mols. in Nature, they are totally insol. in water and they hardly mix with phospholipids in membranes, giving rise to ceramide-enriched domains. In situ enzymic generation, or external addn., of long-chain ceramides in membranes has at least three important effects: (i) the lipid monolayer tendency to adopt a neg. curvature, e.g. through a transition to an inverted hexagonal structure, is increased, (ii) bilayer permeability to aq. solutes is notoriously enhanced, and (iii) transbilayer (flip-flop) lipid motion is promoted. Short-chain ceramides mix much better with phospholipids, promote a pos. curvature in lipid monolayers, and their capacities to increase bilayer permeability or transbilayer motion are very low or non-existent.
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Contreras, F. X.; Basanez, G.; Alonso, A.; Herrmann, A.; Goni, F. M. Biophys. J. 2005, 88, 348
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Siskind, L. J.; Kolesnick, R. N.; Colombini, M. Mitochondrion 2006, 6, 118
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121
Hannun, Y. A.; Obeid, L. M. J. Biol. Chem. 2002, 277, 25847
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Hannun, Y. A.; Obeid, L. M. Nat. Rev. Mol. Cell Biol. 2008, 9, 139
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Principles of bioactive lipid signalling: lessons from sphingolipids
Hannun, Yusuf A.; Obeid, Lina M.
Nature Reviews Molecular Cell Biology (2008), 9 (2), 139-150CODEN: NRMCBP; ISSN:1471-0072. (Nature Publishing Group)
A review. It has become increasingly difficult to find an area of cell biol. in which lipids do not have important, if not key, roles as signaling and regulatory mols. The rapidly expanding field of bioactive lipids is exemplified by many sphingolipids, such as ceramide, sphingosine, sphingosine-1-phosphate (S1P), ceramide-1-phosphate, and lyso-sphingomyelin, which have roles in the regulation of cell growth, death, senescence, adhesion, migration, inflammation, angiogenesis, and intracellular trafficking. Deciphering the mechanisms of these varied cell functions necessitates an understanding of the complex pathways of sphingolipid metab. and the mechanisms that regulate lipid generation and lipid action.
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Gangoiti, P.; Camacho, L.; Arana, L.; Ouro, A.; Granado, M. H.; Brizuela, L.; Casas, J.; Fabrias, G.; Abad, J. L.; Delgado, A.; Gomez-Munoz, A. Prog. Lipid Res. 2010, 49, 316
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Control of metabolism and signaling of simple bioactive sphingolipids: implications in disease
Gangoiti, Patricia; Camacho, Luz; Arana, Lide; Ouro, Alberto; Granado, Maria H.; Brizuela, Leyre; Casas, Josefina; Fabrias, Gemma; Abad, Jose Luis; Delgado, Antonio; Gomez-Munoz, Antonio
Progress in Lipid Research (2010), 49 (4), 316-334CODEN: PLIRDW; ISSN:0163-7827. (Elsevier Ltd.)
A review. Simple bioactive sphingolipids include ceramide, sphingosine and their phosphorylated forms sphingosine 1-phosphate and ceramide 1-phosphate. These mols. are crucial regulators of cell functions. In particular, they play important roles in the regulation of angiogenesis, apoptosis, cell proliferation, differentiation, migration, and inflammation. Decoding the mechanisms by which these cellular functions are regulated requires detailed understanding of the signaling pathways that are implicated in these processes. Most importantly, the development of inhibitors of the enzymes involved in their metab. may be crucial for establishing new therapeutic strategies for treatment of disease.
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Ogretmen, B.; Hannun, Y. A. Nat. Rev. Cancer 2004, 4, 604
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Biologically active sphingolipids in cancer pathogenesis and treatment
Ogretmen, Besim; Hannun, Yusuf A.
Nature Reviews Cancer (2004), 4 (8), 604-616CODEN: NRCAC4; ISSN:1474-175X. (Nature Publishing Group)
A review. Biol. active sphingolipids have key roles in the regulation of several fundamental biol. processes that are integral to cancer pathogenesis. Recent significant progress in understanding biol. active sphingolipid synthesis, specifically within ceramide and sphingosine-1-phosphate (S1P)-mediated pathways, has identified crucial roles for these mols. both in cancer development and progression. Ceramide - a central mol. in sphingolipid metab. - in effect functions as a tumor-suppressor lipid, inducing antiproliferative and apoptotic responses in various cancer cells. Conversely, S1P induces responses that, on aggregate, render S1P a tumor-promoting lipid. These discoveries are paving the way for the advancement of anticancer therapies.
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Hannun, Y. A.; Obeid, L. M. J. Biol. Chem. 2011, 286, 27855
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Oskouian, B.; Saba, J. D. Adv. Exp. Med. Biol. 2010, 688, 185
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Fox, T. E.; Finnegan, C. M.; Blumenthal, R.; Kester, M. Cell. Mol. Life Sci. 2006, 63, 1017
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The clinical potential of sphingolipid-based therapeutics
Fox, T. E.; Finnegan, C. M.; Blumenthal, R.; Kester, M.
Cellular and Molecular Life Sciences (2006), 63 (9), 1017-1023CODEN: CMLSFI; ISSN:1420-682X. (Birkhaeuser Verlag)
A review. The era of sphingolipid-based therapeutics is upon us. A large body of work has been accumulating that demonstrates the distinct biol. roles of sphingolipids in maintaining a homeostatic environment and in responding to environmental stimuli to regulate cellular processes. It is thus necessary to further investigate alterations in sphingolipid-metab. in pathol. conditions and, in turn, try to exploit altered sphingolipid-metabolizing enzymes and their metabolites as therapeutic targets. This review will examine how advances in the fields of drug delivery, drug discovery, synthetic chem., enzyme replacement therapy, immunobiol., infectious disease and nanotechnol. have delivered the potential and promise of utilizing and/or targeting sphingolipid metabolites as therapies for diverse diseases.
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Daido, S.; Kanzawa, T.; Yamamoto, A.; Takeuchi, H.; Kondo, Y.; Kondo, S. Cancer Res. 2004, 64, 4286
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Scarlatti, F.; Bauvy, C.; Ventruti, A.; Sala, G.; Cluzeaud, F.; Vandewalle, A.; Ghidoni, R.; Codogno, P. J. Biol. Chem. 2004, 279, 18384
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Zauner, S.; Ternes, P.; Warnecke, D. Adv. Exp. Med. Biol. 2010, 688, 249
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131
Jennemann, R.; Geyer, R.; Sandhoff, R.; Gschwind, R. M.; Levery, S. B.; Grone, H. J.; Wiegandt, H. Eur. J. Biochem. 2001, 268, 1190
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Glycoinositolphosphosphingolipids (basidiolipids) of higher mushrooms
Jennemann, Richard; Geyer, Rudolf; Sandhoff, Roger; Gschwind, Ruth M.; Levery, Steven B.; Grone, Hermann-Josef; Wiegandt, Herbert
European Journal of Biochemistry (2001), 268 (5), 1190-1205CODEN: EJBCAI; ISSN:0014-2956. (Blackwell Science Ltd.)
The basidiolipids of 6 mushroom spp., i.e. the basidiomycetes Amanita virosa (engl., death cup), Calvatia exipuliformis (engl., puffball), Cantharellus cibarius (engl., chanterelle), Leccinum scabrum (engl., red birch boletus), Lentinus edodes (jap., Shiitake), and Pleurotus ostreatus (engl., oystermushroom), were isolated, and their chem. structures investigated. All glycolipids are structurally related to those of the Agaricales (engl., field mushroom). They are glycoinositolphosphosphingolipids, their ceramide moiety consisting of t18:0-trihydroxysphinganine and an α-hydroxy long-chain fatty acid. In contrast to a previous study, the glycoside anomery of the hexose (mannose) connected to the inositol of all investigated basidiomycete glycolipids, including the basidiolipids of Agaricus bisporus, was detd. unequivocally to be alpha. Therefore, the root structure of all basidiolipids consists of α-D-Manp-2Ins1-[PO4]-Cer. In addn., for some mushroom spp., the occurrence of an inositol substitution position variant, α-Manp-4Ins1-[PO4]-Cer, is shown. The carbohydrate of chanterelle basidiolipids consists solely of mannose, i.e. Cc1, Manα-3 or -6Manα; Cc2, Manα-3(Manα-6)Manα-. All other spp. investigated show extension of the α-mannoside in the 6-position by β-galactoside, which, in some instances, is α-fucosylated in 2-position (Fucα-2)Galβ-6Manα-. Further sugar chain elongation at the β-galactoside may be in 3- and/or 6-position by α-galactoside, e.g. Ce4, Po2, Galα-3-(Galα-6)(Fucα-2)Galβ-6Manα-, whereas A. virosa, Av-3, has a more complex, highly α-fucosylated terminus, Galα-3 (Fucα-2)(Fucα-6)Galα-2(Galα-3)Galβ-6Manα-. L. edodes basidiolipids show further elongation by α-mannoside, e.g. Le3, Manα-2Manα-6Galα-3(Fucα-2)Galβ-6Manα-, C. exipuliformis glycolipid by α-glucoside, i.e. Ce3, Glcα-6Galβ-6Manα-. Basidiolipid Ls1 from L. scabrum, notably, has a 3-α-mannosylated α-fucose, i.e. Galα-6(Manα-3Fucα-2)Galα-6Galβ-6Manα-. In conclusion, basidiolipids, though identical in their ceramide constitution, display wide and systematic mushroom species dependent variabilities of their chem. structures.
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Levery, S. B.; Toledo, M. S.; Straus, A. H.; Takahashi, H. K. Rapid Commun. Mass Spectrom. 2001, 15, 2240
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Comparative analysis of glycosylinositol phosphorylceramides from fungi by electrospray tandem mass spectrometry with low-energy collision-induced dissociation of Li+ adduct ions
Levery, Steven B.; Toledo, Marcos S.; Straus, Anita H.; Takahashi, Helio K.
Rapid Communications in Mass Spectrometry (2001), 15 (23), 2240-2258CODEN: RCMSEF; ISSN:0951-4198. (John Wiley & Sons Ltd.)
Glycosylinositol phosphorylceramides (GIPCs) are a class of acidic glycosphingolipids (GSLs) expressed by fungi, plants, and certain parasitic organisms, but not found in cells or tissues of mammals or other higher animals. Recent characterizations of fungal GIPCs point to an emerging diversity which could rival that already known for mammalian GSLs, and which can be expected to present a multitude of challenges for the anal. chemist. Previously, the use of Li+ cationization, in conjunction with electrospray ionization mass spectrometry (ESI-MS) and low-energy collision-induced dissocn. tandem mass spectrometry (ESI-MS/CID-MS), was found to be particularly effective for detailed structural anal. of monohexosylceramides (cerebrosides) from a variety of sources, including fungi, esp. minor components present in mixts. at extremely low abundance. In applying Li+ cationization to characterization of GIPCs, a substantial increase in both sensitivity and fragmentation was obsd. on collision-induced dissocn. of [M + Li]+ vs. [M + Na]+ for the same components analyzed under similar conditions, similar to results obtained previously with cerebrosides. Mol. adduct fragmentation patterns were found to be systematic and characteristic for both the glycosylinositol and ceramide moieties with or without phosphate. Interestingly, significant differences were obsd. in fragmentation patterns when comparing GIPCs having Manα1→2 vs. Manα1→6Ins core linkages. In addn., it was useful to perform tandem product ion scans on primary fragments generated in the orifice region, equiv. to ESI-(CID-MS)2 mode. Finally, precursor ion scanning from appropriate glycosylinositol phosphate product ions yielded clean mol. ion profiles in the presence of obscuring impurity peaks. The methods were applied to detailed characterization of GIPC fractions of increasing structural complexity from a variety of fungi, including a non-pathogenic Basidiomycete (mushroom), Agaricus blazei, and pathogenic Euascomycete species such as Aspergillus fumigatus, Histoplasma capsulatum, and Sporothrix schenckii. The anal. confirmed a remarkable diversity of GIPC structures synthesized by the dimorphic S. schenckii, as well as differential expression of both glycosylinositol and ceramide structures in the mycelium and yeast forms of this mycopathogen. Mass spectrometry also established that the ceramides of some A. fumigatus GIPC fractions contain very little 2-hydroxylation of the long-chain fatty-N-acyl moiety, a feature that is not generally obsd. with fungal GIPCs.
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Levery, S. B. Methods Enzymol. 2005, 405, 300
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Glycosphingolipid structural analysis and glycosphingolipidomics
Levery, Steven B.
Methods in Enzymology (2005), 405 (Mass Spectrometry: Modified Proteins and Glycoconjugates), 300-369CODEN: MENZAU; ISSN:0076-6879. (Elsevier)
A review. Sphingosines, or sphingoids, are a family of naturally occurring long-chain hydrocarbon derivs. sharing a common 1,3-dihydroxy-2-amino-backbone motif. The majority of sphingolipids, as their derivs. are collectively known, can be found in cell membranes in the form of amphiphilic conjugates, each composed of a polar head group attached to an N-acylated sphingoid, or ceramide. Glycosphingolipids (GSLs), which are the glycosides of either ceramide or myo-inositol-(1-O)-phosphoryl-(O-1)-ceramide, are a structurally and functionally diverse sphingolipid subclass; GSLs are ubiquitously distributed among all eukaryotic species and are found in some bacteria. Since GSLs are secondary metabolites, direct and comprehensive anal. (metabolomics) must be considered an essential complement to genomic and proteomic approaches for establishing the structural repertoire within an organism and deducing its possible functional roles. The glycosphingolipidome clearly comprises an important and extensive subset of both the glycome and the lipidome, but the complexities of GSL structure, biosynthesis, and function form the outlines of a considerable anal. problem, esp. since their structural diversity confers by extension an enormous variability with respect to physicochem. properties. This chapter covers selected developments and applications of techniques in mass spectrometric (MS) that have contributed to GSL structural anal. and glycosphingolipidomics since 1990. Sections are included on basic characteristics of ionization and fragmentation of permethylated GSLs and of lithium-adducted nonderivatized GSLs under pos.-ion electrospray ionization mass spectrometry (ESI-MS) and collision-induced mass spectrometry (CID-MS) conditions; on the anal. of sulfatides, mainly using neg.-ion techniques; and on selected applications of ESI-MS and matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) to emerging GSL structural, functional, and anal. issues. The latter section includes a particular focus on evolving techniques for anal. of gangliosides, GSLs contg. sialic acid, as well as on characterizations of GSLs from selected nonmammalian eukaryotes, such as dipterans, nematodes, cestodes, and fungi. Addnl. sections focus on the issue of whether it is better to leave GSLs intact or remove the ceramide; on development and uses of thin-layer chromatog. (TLC) blotting and TLC-MS techniques; and on emerging issues of high-throughput anal., including the use of flow injection, liq. chromatog. mass spectrometry (LC-MS), and capillary electrophoresis mass spectrometry (CE-MS).
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Lamour, N. F.; Stahelin, R. V.; Wijesinghe, D. S.; Maceyka, M.; Wang, E.; Allegood, J. C.; Merrill, A. H., Jr.; Cho, W.; Chalfant, C. E. J. Lipid Res. 2007, 48, 1293
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Hinkovska-Galcheva, V.; Boxer, L. A.; Kindzelskii, A.; Hiraoka, M.; Abe, A.; Goparju, S.; Spiegel, S.; Petty, H. R.; Shayman, J. A. J. Biol. Chem. 2005, 280, 26612
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Activation of mTOR and RhoA is a major mechanism by which ceramide 1-phosphate stimulates macrophage proliferation
Gangoiti, Patricia; Arana, Lide; Ouro, Alberto; Granado, Maria H.; Trueba, Miguel; Gomez-Munoz, Antonio
Cellular Signalling (2011), 23 (1), 27-34CODEN: CESIEY; ISSN:0898-6568. (Elsevier)
This study tested the hypothesis that Ceramide 1-phosphate (C1P) stimulates macrophage proliferation through activation of the mammalian target of rapamycin (mTOR). We first reported that C1P is mitogenic for fibroblasts and macrophages, but the mechanisms whereby it stimulates cell proliferation are incompletely understood. Here we demonstrate that C1P causes phosphorylation of mTOR in primary (bone marrow-derived) macrophages. Activation of this kinase was tested my measuring the phosphorylation state of its downstream target p70S6K after treatment with C1P. These actions were dependent upon prior activation of phosphoinositide 3 kinase (PI3-K), as selective inhibition of this kinase blocked mTOR phosphorylation and activation. In addn., C1P caused phosphorylation of PRAS40, a component of the mTOR complex 1 (mTORC1) that is absent in mTORC2. Furthermore, inhibition of the small G protein Ras homolog enriched in brain (Rheb), which is also a specific component of mTORC1, with FTI277, completely blocked C1P-stimulated mTOR phosphorylation, DNA synthesis and macrophage growth. In addn., C1P caused phosphorylation of another Ras homolog gene family member, RhoA, which is also involved in cell proliferation. Interestingly, inhibition of the RhoA downstream effector RhoA-assocd. kinase (ROCK) also blocked C1P-stimulated mTOR and cell proliferation. It can be concluded that mTORC1, and RhoA/ROCK are essential components of the mechanism whereby C1P stimulates macrophage proliferation.
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Sphingolipids in inflammation: Roles and implications
Pettus, B. J.; Chalfant, C. E.; Hannun, Y. A.
Current Molecular Medicine (2004), 4 (4), 405-418CODEN: CMMUBP; ISSN:1566-5240. (Bentham Science Publishers Ltd.)
A review. Sphingolipids, historically described as potential reservoirs for bioactive lipids, presently define a new family of cellular mediators, joining the well-established glycerolipid-derived mediators of signal transduction such as diacylglycerol, phosphatidylinositides, and eicosanoids. Sphingolipid metab. is clearly involved in the regulation of cell growth, differentiation, and programmed cell death. Indeed, a majority of the greater than four thousand studies conducted on sphingolipids during the past five years were investigations of the role of sphingolipids as cellular bioregulators. Studies spanning more than a decade have shown multiple interactions and intersections of the sphingolipid-mediated pathways and the eicosanoid pathway. This review will discuss the emerging mechanisms by which sphingolipids induce inflammatory responses via the eicosanoid pathway in addn. to linking previous literature on sphingolipids and inflammation with newer findings of distinct roles for sphingosine-1-phosphate in regulating cyclooxygenase-2 and ceramide-1-phosphate in the regulation of cytosolic phospholipase A2α. Finally, the relationship between bioactive sphingolipids and inflammation is discussed.
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Gubern, A.; Barcelo-Torns, M.; Barneda, D.; Lopez, J. M.; Masgrau, R.; Picatoste, F.; Chalfant, C. E.; Balsinde, J.; Balboa, M. A.; Claro, E. J. Biol. Chem. 2009, 284, 32359
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Barenholz, Y.; Thompson, T. E. Chem. Phys Lipids 1999, 102, 29
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Barenholz, Y. Subcell Biochem 2004, 37, 167
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Sphingomyelin and cholesterol: from membrane biophysics and rafts to potential medical applications
Barenholz, Yechezkel
Subcellular Biochemistry (2004), 37 (Membrane Dynamics and Domains), 167-215CODEN: SBCBAG; ISSN:0306-0225. (Kluwer Academic/Plenum Publishers)
A review. The preferential sphingomyelin-cholesterol interaction which results from the structure and the mol. properties of these two lipids seems to be the physicochem. basis for the formation and maintenance of cholesterol/sphingolipid-enriched nano- and micro-domains (referred to as membrane "rafts") in the plane of plasma and other organelle (i.e., Golgi) membranes. This claim is supported by much exptl. evidence and also by theor. considerations. However, although there is a large vol. of information about these rafts regarding their lipid and protein compn., their size, and their dynamics, there is still much to be clarified on these issues, as well as on how rafts are formed and maintained. It is well accepted now that the lipid phase of the rafts is the liq. ordered (LO) phase. However, other (non-raft) parts of the membrane may also be in the LO phase. There are indications that the raft LO phase domains are more tightly packed than the non-raft LO phase, possibly due to intermol. hydrogen bonding involving sphingolipid and cholesterol. This also explains why the former are detergent-resistant membranes (DRM), while the non-raft LO phase domains are detergent-sol. (sensitive) membranes (DSM). Recent findings suggest that protein-protein interactions such as crosslinking can be controlled by protein distribution between raft and non-raft domains, and, as well, these interactions affect raft size distribution. The cholesterol/sphingomyelin-enriched rafts seem to be involved in many biol. processes, mediated by various receptors, as exemplified by various lipidated glycosylphosphatidylinositol (GPI)- and acyl chain-anchored proteins that reside in the rafts. The rafts serve as signaling platforms in the cell. Various pathogens (viruses and toxins) utilize the raft domains on the host cell membrane as a port of entry, site of assembly (viruses), and port of exit (viral budding). Existence and maintenance of cholesterol-sphingomyelin rafts are dependent on the level of membrane cholesterol and sphingomyelin. This explains why redn. of cholesterol level - either through reverse cholesterol transport, using cholesterol acceptors such as β-cyclodextrin, or through cholesterol biosynthesis inhibition using statins interferes with many processes which involve rafts and can be applied to treating raft-related infections and diseases. Detailed elucidation of raft structure and function will improve understanding of biol. membrane compn.-structure-function relationships and also may serve as a new avenue for the development of novel treatments for major diseases, including viral infections, neurodegenerative diseases (Alzheimer's), atherosclerosis, and tumors.
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Koivusalo, M.; Jansen, M.; Somerharju, P.; Ikonen, E. Mol. Biol. Cell 2007, 18, 5113
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Endocytic trafficking of sphingomyelin depends on its acyl chain length
Koivusalo, Mirkka; Jansen, Maurice; Somerharju, Pentti; Ikonen, Elina
Molecular Biology of the Cell (2007), 18 (12), 5113-5123CODEN: MBCEEV; ISSN:1059-1524. (American Society for Cell Biology)
To study the principles of endocytic lipid trafficking, we introduced pyrene sphingomyelins (PyrSMs) with varying acyl chain lengths and domain partitioning properties into human fibroblasts or HeLa cells. We found that a long-chain, ordered-domain preferring PyrSM was targeted Hrs and Tsg101 dependently to late endosomal compartments and recycled to the plasma membrane in an NPC1- and cholesterol-dependent manner. A short-chain, disordered domain preferring PyrSM recycled more effectively, by using Hrs-, Tsg101- and NPC1-independent routing that was insensitive to cholesterol loading. Similar chain length-dependent recycling was obsd. for unlabeled sphingomyelins (SMs). The findings (1) establish acyl chain length as an important determinant in the endocytic trafficking of SMs, (2) implicate ESCRT complex proteins and NPC1 in the endocytic recycling of ordered domain lipids to the plasma membrane, and (3) introduce long-chain PyrSM as the first fluorescent lipid tracing this pathway.
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Shogomori, H.; Kobayashi, T. Biochim. Biophys. Acta 2008, 1780, 612
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Occurrence and biosynthesis of ceramide phosphorylethanolamine in chicken and rat liver
Muehlenberg, Bernd A.; Sribney, Michael; Duffe, Marilyn K.
Canadian Journal of Biochemistry (1972), 50 (2), 166-73CODEN: CJBIAE; ISSN:0008-4018.
Ceramide phosphorylethanolamine occurs in chicken and rat liver, and an enzyme (CDP-ethanolamine:ceramide ethanol-aminephosphotransferase) (I) has been found in a no. of tissues which catalyzes the biosynthesis of this lipid. The enzyme catalyzes the transfer of the phosphorylethanolamine moiety of CDP-ethanolamine to the free primary hydroxyl group of a ceramide (N-acylsphingosine). The chicken liver enzyme requires 0.010M Mn2+ for optimal activity and has a pH optimum of 7.7. The Km for the substrate N-octanoyl-threo-sphingosine was 2.5 × 10-4 M. A study of the effect of increasing CDP-ethanolamine concn. on the reaction rate indicates from sigmoid kinetics that the coenzyme modulates and possibly regulates I activity. The enutilize the unnatural threo isomer of N-acylsphingosines (threoceramides) as acceptors for the phosphorylethanolamine moiety of CDP-ethanolamine.
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Vacaru, A. M.; Tafesse, F. G.; Ternes, P.; Kondylis, V.; Hermansson, M.; Brouwers, J. F.; Somerharju, P.; Rabouille, C.; Holthuis, J. C. J. Cell Biol. 2009, 185, 1013
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Masood, M. A.; Yuan, C.; Acharya, J. K.; Veenstra, T. D.; Blonder J. Anal. Biochem. 2010, 400, 259
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Quantitation of ceramide phosphorylethanolamines containing saturated and unsaturated sphingoid base cores
Masood, M. Athar; Yuan, Changqing; Acharya, Jairaj K.; Veenstra, Timothy D.; Blonder, Josip
Analytical Biochemistry (2010), 400 (2), 259-269CODEN: ANBCA2; ISSN:0003-2697. (Elsevier B.V.)
Sphingomyelin (SM) and ceramide-phosphoethanolamines (cer-PEs) are related lipids present in mammals and insects, resp. Owing to the crit. roles that cer-PEs play in eukaryotic cellular function, there is a need to develop methods that provide accurate quantitation of these compds. Results obtained in this study demonstrate that Drosophila contains cer-PEs with unsatd. sphingoid base cores as well as low levels of cer-PEs that possess satd. sphingoid base cores. Specifically, the method developed in this study enabled the quantitation of picogram amts. of cer-PE contg. both unsatd. d14:1Δ4 and d16:1Δ4 and satd. d14:0 sphingoid base cores. Using this method, cer-PE compds. with both satd. and unsatd. sphingoid base cores were initially identified by neutral loss scanning, followed by quantitation using selected reaction monitoring (SRM) scans. The SRM scans measured a product ion originating from the sphingoid base backbone, rather than from the head group, increasing the specificity and sensitivity of the quantitation measurement.
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Recently discovered functions of glucosylceramides in plants and fungi
Warnecke, D.; Heinz, E.
Cellular and Molecular Life Sciences (2003), 60 (5), 919-941CODEN: CMLSFI; ISSN:1420-682X. (Birkhaeuser Verlag)
A review. Glycosphingolipids are ubiquitous membrane lipids of eukaryotic organisms and a few bacteria. Whereas inositol-contg. glycosphingolipids are restricted to plants and fungi, galactosylceramide occurs only in fungi and animals. In contrast, glucosylceramide is the unique glycosphingolipid which plants, fungi, and animals have in common. However, there are specific differences in the structure of the ceramide backbone of glucosylceramides from these organisms. A comparison of the structural features and the biosynthesis of glucosylceramides from plants, fungi and animals has contributed to an understanding of their functions, which so far have been analyzed mainly in animals. The availability of nearly all genes involved in the biosynthesis of glucosylceramides has enabled the specific manipulation of glycosphingolipid metab. by techniques of forward and reverse genetics. The application of this approach to unicellular organisms such as yeasts, multicellular filamentous fungi, as well as to complex organisms like plants has revealed common and different glucosylceramide functions in these organisms. These glycolipids play a role both in intracellular processes and in cell-to-cell interactions. These interactions may occur between cells of a multicellular organism or between cells of different species, as in host-pathogen interactions.
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The fate and function of glycosphingolipid glucosylceramide
van Meer, Gerrit; Wolthoorn, Jasja; Degroote, Sophie
Philosophical Transactions of the Royal Society of London, Series B: Biological Sciences (2003), 358 (1433), 869-873CODEN: PTRBAE; ISSN:0962-8436. (Royal Society)
A review. In higher eukaryotes, glucosylceramide is the simplest member and precursor of a fascinating class of membrane lipids, the glycosphingolipids. These lipids display an astounding variation in their carbohydrate head groups, suggesting that glycosphingolipids serve specialized functions in recognition processes. It is now realized that they are organized in signaling domains on the cell surface. They are of vital importance as, in their absence, embryonal development is inhibited at an early stage. Remarkably, individual cells can live without glycolipids, perhaps because their survival does not depend on glycosphingolipid-mediated signaling mechanisms. Still, these cells suffer from defects in intracellular membrane transport. Various membrane proteins do not reach their intracellular destination, and, indeed, some intracellular organelles do not properly differentiate to their mature stage. The fact that glycosphingolipids are required for cellular differentiation suggests that there are human diseases resulting from defects in glycosphingolipid synthesis. In addn., the same cellular differentiation processes may be affected by defects in the degrdn. of glycosphingolipids. At the cellular level, the pathol. of glycosphingolipid storage diseases is not completely understood. Cell biol. studies on the intracellular fate and function of glycosphingolipids may open new ways to understand and defeat not only lipid storage diseases, but perhaps other diseases that have not been connected to glycosphingolipids so far.
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Liu, Y. Y.; Patwardhan, G. A.; Xie, P.; Gu, X.; Giuliano, A. E.; Cabot, M. C. Int. J. Oncol. 2011, 39, 425
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Glucosylceramide synthase, a factor in modulating drug resistance, is overexpressed in metastatic breast carcinoma
Liu, Yong-Yu; Patwardhan, Gauri A.; Xie, Ping; Gu, Xin; Giuliano, Armando E.; Cabot, Myles C.
International Journal of Oncology (2011), 39 (2), 425-431CODEN: IJONES; ISSN:1019-6439. (International Journal of Oncology)
Drug resistance causes treatment failure in approx. 50% of breast cancer patients with chemotherapy. Overexpression of glucosylceramide synthase (GCS) confers drug resistance in cancer cells, and suppression of GCS sensitizes cancers to chemotherapy in preclin. studies. Thus, GCS becomes a potential target to reverse drug resistance; however, little is known about GCS expression levels in normal tissues and whether GCS overexpression is assocd. with metastatic cancers. Herewith, we report our studies in GCS expression levels and breast cancer from patients. GCS levels were analyzed using cancer profiling arrays, breast cancer histo-arrays and quant. RT-PCR in tumor tissues. We found that breast (18 exp. index) and other hormone-dependent organs (testis, cervix, ovary, prostate) displayed the lowest levels of GCS mRNA, whereas liver (52 exp. index) and other organs (kidney, bladder, stomach) displayed the highest levels of GCS. GCS mRNA levels were significantly elevated in tumors of breast, cervix, rectum and small intestine, as compared to each paired normal tissue. In mammary tissue, GCS overexpression was detected in breast cancers with metastasis, but not in benign fibroadenoma or primary tumors. GCS overexpression was coincident with HER2 expression (γ2 = 0.84) in ER-neg. breast adenocarcinoma. In tumor specimens, GCS mRNA was elevated by 4-fold and significantly assocd. with stage III (5/7), lymph node-pos. (7/8) and estrogen receptor-pos. breast cancers (7/9). GCS expression was significantly and selectively elevated in breast cancer, in particular in metastatic disease. GCS overexpression was highly assocd. with ER-pos. and HER2-pos. breast cancer with metastasis. Although a small study, these data suggest that GCS may be a prognostic indicator and potential target for the treatment of chemotherapy-refractory breast cancer.
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Lalazar, G.; Ben Ya’acov, A.; Livovsky, D. M.; El Haj, M.; Pappo, O.; Preston, S.; Zolotarov, L.; Ilan, Y. Am. J. Pathol. 2009, 174, 1390
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β-glycoglycosphingolipid-induced alterations of the STAT signaling pathways are dependent on CD1d and the lipid raft protein flotillin-2
Lalazar, Gadi; Ben Ya'acov, Ami; Livovsky, Dan M.; El Haj, Madi; Pappo, Orit; Preston, Sarah; Zolotarov, Lidya; Ilan, Yaron
American Journal of Pathology (2009), 174 (4), 1390-1399CODEN: AJPAA4; ISSN:0002-9440. (American Society for Investigative Pathology)
β-Glucosylceramide has been shown to affect natural killer T cell function in models of inflammation. We, therefore, investigated the effects of different β-glycosphingolipids, including β-glucosylceramide, on STAT (signal transducers and activators of transcription) signaling pathways and detd. whether these effects were mediated by lipid raft microdomains and/or CD1d mols. The effects of α- and β-structured ligands on the lipid raft protein flotillin-2 were studied in both natural killer T hybridoma cells and leptin-deficient mice. To det. whether CD1d was involved in the effects of the β-glycosphingolipids, an anti-CD1d blocking antibody was used in a cell proliferation assay system. The downstream effects on the protein phosphorylation levels of STAT1, STAT3, and STAT6 were examd. in both immune-mediated hepatitis and hepatoma models. The effects of β-glycosphingolipids on the STAT signaling pathways were found to be dependent on CD1d. Lipid rafts were affected by both the dose and ratio of the β-glycosphingolipids and the acyl chain length, and these effects were followed by downstream effects on STAT proteins. Our results show that β-glycosphingolipids have beneficial effects in natural killer T cell-dependent immune-mediated metabolic and malignant animal models in vivo.
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Boggs, J. M.; Gao, W.; Zhao, J.; Park, H. J.; Liu, Y.; Basu, A. FEBS Lett. 2010, 584, 1771
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Venkataswamy, M. M.; Porcelli, S. A. Semin. Immunol. 2010, 22, 68
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Lipid and glycolipid antigens of CD1d-restricted natural killer T cells
Venkataswamy, Manjunatha M.; Porcelli, Steven A.
Seminars in Immunology (2010), 22 (2), 68-78CODEN: SEIME2; ISSN:1044-5323. (Elsevier B.V.)
A review. In spite of their relatively limited antigen receptor repertoire, CD1d-restricted NKT cells recognize a surprisingly diverse range of lipid and glycolipid antigens. Recent studies of natural and synthetic CD1d-presented antigens provide an increasingly detailed picture of how the specific structural features of these lipids and glycolipids influence their ability to be presented to NKT cells and stimulate their diverse immunol. functions. Particularly for synthetic analogs of α-galactosylceramides which have been the focus of intense recent investigation, it is becoming clear that the design of glycolipid antigens with the ability to precisely control the specific immunol. activities of NKT cells is likely to be feasible. The emerging details of the mechanisms underlying the structure-activity relationship of NKT cell antigens will assist greatly in the design and prodn. of immunomodulatory agents for the precise manipulation of NKT cells and the many other components of the immune system that they influence.
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Goff, R. D.; Gao, Y.; Mattner, J.; Zhou, D.; Yin, N.; Cantu, C., 3rd; Teyton, L.; Bendelac, A.; Savage, P. B. J. Am. Chem. Soc. 2004, 126, 13602
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Yu, K. O.; Im, J. S.; Molano, A.; Dutronc, Y.; Illarionov, P. A.; Forestier, C.; Fujiwara, N.; Arias, I.; Miyake, S.; Yamamura, T.; Chang, Y. T.; Besra, G. S.; Porcelli, S. A. Proc. Natl. Acad. Sci. U.S.A. 2005, 102, 3383
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Ishizuka, I. Prog. Lipid Res. 1997, 36, 245
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Chemistry and functional distribution of sulfoglycolipids
Ishizuka, Ineo
Progress in Lipid Research (1997), 36 (4), 245-319CODEN: PLIRDW; ISSN:0163-7827. (Elsevier Science Ltd.)
A review, with 667 refs. The topics discussed include: isolation and purifn.; anal. methods; structure; functional distribution; biosynthesis and biodegrdn.; and interaction with biomols.
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Popovic, Z. V.; Sandhoff, R.; Sijmonsma, T. P.; Kaden, S.; Jennemann, R.; Kiss, E.; Tone, E.; Autschbach, F.; Platt, N.; Malle, E.; Grone, H. J. J. Immunol. 2007, 179, 6770
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Merten, M.; Thiagarajan, P. Z. Kardiol. 2004, 93, 855
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P-selectin in arterial thrombosis
Merten, M.; Thiagarajan, P.
Zeitschrift fuer Kardiologie (2004), 93 (11), 855-863CODEN: ZKRDAX; ISSN:0300-5860. (Steinkopff Verlag)
A review. P-selectin is a transmembrane protein present in the a granules of platelets and the Weibel-Palade bodies of endothelial cells. Following activation, it is rapidly translocated to the cell surface. P-selectin expression in platelets has been shown to be elevated in disorders assocd. with arterial thrombosis such as coronary artery disease, acute myocardial infarction, stroke, and peripheral artery disease. P-selectin mediates rolling of platelets and leukocytes on activated endothelial cells as well as interactions of platelets with leukocytes. Platelet P-selectin interacts with P-selectin glycoprotein ligand-1 (PSGL-1) on leukocytes to form platelet-leukocyte aggregates. Furthermore, this interaction of P-selectin with PSGL-1 induces the upregulation of tissue factor, several cytokines in leukocytes and the prodn. of procoagulant microparticles, thereby contributing to a prothrombotic state. P-selectin is also involved in platelet-platelet interactions, i.e. platelet aggregation which is a major factor in arterial thrombosis. P-selectin interacts with platelet sulfatides, thereby stabilizing initial platelet aggregates formed.
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Shikata, K.; Suzuki, Y.; Wada, J.; Hirata, K.; Matsuda, M.; Kawashima, H.; Suzuki, T.; Iizuka, M.; Makino, H.; Miyasaka, M. J. Pathol. 1999, 188, 93
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L-selectin and its ligands mediate infiltration of mononuclear cells into kidney interstitium after ureteric obstruction
Shikata, Kenichi; Suzuki, Yasuo; Wada, Jun; Hirata, Kyoji; Matsuda, Mitsuhiro; Kawashima, Hiroto; Suzuki, Takashi; Iizuka, Masako; Makino, Hirofumi; Miyasaka, Masayuki
Journal of Pathology (1999), 188 (1), 93-99CODEN: JPTLAS; ISSN:0022-3417. (John Wiley & Sons Ltd.)
It was previously reported that the L-selectin ligands detected by a rat L-selectin and human IgG chimeric mol. (rLEC-IgG) are expressed in the distal tubules of the kidney, where no leukocyte traffic is seen under physiol. conditions. In the present study, the role of L-selectin ligands in leukocyte infiltration into the kidney interstitium was investigated using a rat ureteric obstruction model. After ligation of the ureter, ligands for L-selectin rapidly disappeared from tubular epithelial cells and were relocated to the interstitium and peritubular capillary walls, where infiltration of monocytes and CD8+ T cells subsequently occurred. Mononuclear cell infiltration was significantly inhibited by i.v. injection of a neutralizing monoclonal antibody (MAb) against L-selectin, indicating the possible involvement of an L-selectin-mediated pathway. Interestingly, immunohistochem. studies with a MAb against sulfatide showed that the distribution of sulfatide, known to be one of the candidates of L-selectin ligand, was almost indistinguishable from the staining pattern of rLEC-IgG in both normal and ureteric obstructed kidneys, suggesting that sulfatide and/or related mol.(s) relocated to the renal interstitium were recognized by leukocyte L-selectin, leading to interstitial leukocyte infiltration. In line with this notion, i.v. injection of sulfatide markedly inhibited leukocyte infiltration, suggesting that L-selectin-sulfatide interaction may play a pivotal role in interstitial leukocyte infiltration in the kidney following ureteric obstruction.
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Kobayashi, T.; Honke, K.; Miyazaki, T.; Matsumoto, K.; Nakamura, T.; Ishizuka, I.; Makita, A. J. Biol. Chem. 1994, 269, 9817
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Don, A. S.; Rosen, H. Biochem. Biophys. Res. Commun. 2009, 380, 87
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Morichika, H.; Hamanaka, Y.; Tai, T.; Ishizuka, I. Cancer 1996, 78, 43
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Hiraiwa, N.; Fukuda, Y.; Imura, H.; Tadano-Aritomi, K.; Nagai, K.; Ishizuka, I.; Kannagi, R. Cancer Res. 1990, 50, 2917
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177
Sakakibara, N.; Gasa, S.; Kamio, K.; Makita, A.; Nonomura, K.; Togashi, M.; Koyanagi, T.; Hatae, Y.; Takeda, K. Cancer Lett. 1991, 57, 187
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177
Distinctive glycolipid patterns in Wilms' tumor and renal cell carcinoma
Sakakibara, N.; Gasa, Shinsei; Kamio, K.; Makita, A.; Nonomura, K.; Togashi, M.; Koyanagi, T.; Hatae, Y.; Takeda, K.
Cancer Letters (Shannon, Ireland) (1991), 57 (3), 187-92CODEN: CALEDQ; ISSN:0304-3835.
Glycolipid patterns were analyzed chromatog. in Wilms' tumor and renal-cell carcinoma tissues and compared with those of uninvolved tissue. Ganglioside GM3 was increased in both cancer tissues, whereas sulfatides accumulated only in renal-cell carcinoma, as reported earlier. Neolactotetraosylceramide was detected in both cancer tissues, but not in the uninvolved kidney tissues. In four cases of Wilms' tumors, only a low level of sulfotransferase towards galactosylceramide was found in one case, while no activity was detected in the three other cases. Present results show that the increased sulfatide(s) in the renal cell carcinoma and the deficiency of the sulfatides in Wilms' tumors appear to be biochem. characteristics of histol. differentt carcinomas.
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Li, J.; Pearl, D. K.; Pfeiffer, S. E.; Yates, A. J. J. Neurosci. Res. 1994, 39, 148
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178
Patterns of reactivity with anti-glycolipid antibodies in human primary brain tumors
Li, J.; Pearl, D. K.; Pfeiffer, S. E.; Yates, A. J.
Journal of Neuroscience Research (1994), 39 (2), 148-58CODEN: JNREDK; ISSN:0360-4012.
Antibodies against carbohydrates of three glycolipids were used to det. patterns of immunohistochem. reactivity of histol. identifiable cell subpopulations in 101 human primary brain tumors. For all tumor types fibrillary cells, polar cells, and gemistocytes (commonly seen in astrocytomas and ependymomas) stained more frequently for galactosylcerebroside with mAbO1 than small tumor cells and macrophages. Frequency of staining for sulfatide with mAbO4 was fibrillary > polar > small cells = macrophages. Gemistocytes stained more frequently with mAbO4 than polar cells in all tumors except low grade astrocytomas. These data indicate that tumors classified on histol. grounds as astrocytic are often stained with antibodies that recognize oligodendrocytes and their progenitors. Thus, anti-glycolipid antibodies used in the study of developmental lineage may offer useful tools for classification of human brain tumors. Staining of fibrillary cells, polar cells, and gemistocytes for paragloboside directly with mAb F1H11 was much less common than with mAbO1, but this increased by pretreatment of the tissues with neuraminidase (F1H11+N). Of particular note was the finding that small tumor cells frequently stained with F1H11+N. Evidence that these were not macrophages was obtained using double immunostaining with F1H11+N and anti-macrophage antibodies. In astrocytomas the frequency of small tumor cells immunostained with F1H11+N was high grade > anaplastic > low grade, demonstrating a correlation of this tumor cell population with more aggressive astrocytomas. Thus, immunostaining with F1H11+N may be of value in identifying small, anaplastic tumor cells, esp. in small biopsies or tissue taken adjacent to the main tumor mass.
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Gnewuch, C.; Jaques, G.; Havemann, K.; Wiegandt, H. Int. J. Cancer Suppl 1994, 8, 125
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179
Re-assessment of acidic glycosphingolipids in small-cell-lung-cancer tissues and cell lines
Gnewuch C; Jaques G; Havemann K; Wiegandt H
International journal of cancer. Supplement = Journal international du cancer. Supplement (1994), 8 (), 125-6 ISSN:0898-6924.
The occurrence of tumor-associated glycosphingolipids (GSLs) has been documented in a variety of cancer tissues (Hakomori, 1984, 1985, 1989). In the case of small-cell lung cancer (SCLC), the monosialoganglioside IV2Fuc-II3NeuAc-Gg4Cer (Fuc-GM1; short notations of gangliosides are according to Svennerholm, 1963), first described from bovine liver (Wiegandt, 1973), was found to be a unique tumor-associated GSL (Nilsson et al., 1984). It is present in up to 90% of all SCLC cases as compared with 25% frequency in non-SCLC, and no occurrence in normal lung (Brezicka et al., 1989, 1992). Thus, Fuc-GM1 may represent a suitable target antigen for immunotherapy of SCLC, and successful experiments have been performed showing tumor-cell killing by monoclonal antibodies (MAbs) against Fuc-GM1, both in vitro and, in a mouse model, in vivo (Brezicka et al., 1991). However, an effective tumor vaccination in humans would require this antigen to be expressed by the primary tumor and also by all metastases. The co-expression of Fuc-GM1 has already been reported in primary tumors and in most but not all metastases of SCLC (Hanquing et al., 1986; Nilsson et al., 1986; Brezicka et al., 1989). In view of the significance this ganglioside may have for possible immunotherapeutical approaches to SCLC and of the difficulty in obtaining a sufficient number of samples for analysis, a re-assessment of Fuc-GM1 expression was made in SCLC primary tumors and their metastases, as well as in established SCLC cell lines. In addition, the possible presence of such gangliosides, that might help to explain the selective tetanus-toxin binding of SCLC cells (Critchley et al., 1986; Heymanns et al., 1989) was investigated. Finally, the typical occurrence of sulfatide in all SCLC tissues and cell lines could be established.
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Liu, Y.; Chen, Y.; Momin, A.; Shaner, R.; Wang, E.; Bowen, N. J.; Matyunina, L. V.; Walker, L. D.; McDonald, J. F.; Sullards, M. C.; Merrill, A. H., Jr. Mol. Cancer 2010, 9, 186
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180
Elevation of sulfatides in ovarian cancer: an integrated transcriptomic and lipidomic analysis including tissue-imaging mass spectrometry
Liu Ying; Chen Yanfeng; Momin Amin; Shaner Rebecca; Wang Elaine; Bowen Nathan J; Matyunina Lilya V; Walker L Deette; McDonald John F; Sullards M Cameron; Merrill Alfred H Jr
Molecular cancer (2010), 9 (), 186 ISSN:.
BACKGROUND: Sulfatides (ST) are a category of sulfated galactosylceramides (GalCer) that are elevated in many types of cancer including, possibly, ovarian cancer. Previous evidence for elevation of ST in ovarian cancer was based on a colorimetric reagent that does not provide structural details and can also react with other lipids. Therefore, this study utilized mass spectrometry for a structure-specific and quantitative analysis of the types, amounts, and tissue localization of ST in ovarian cancer, and combined these findings with analysis of mRNAs for the relevant enzymes of ST metabolism to explore possible mechanisms. RESULTS: Analysis of 12 ovarian tissues graded as histologically normal or having epithelial ovarian tumors by liquid chromatography electrospray ionization-tandem mass spectrometry (LC ESI-MS/MS) established that most tumor-bearing tissues have higher amounts of ST. Because ovarian cancer tissues are comprised of many different cell types, histological tissue slices were analyzed by matrix-assisted laser desorption ionization-tissue-imaging MS (MALDI-TIMS). The regions where ST were detected by MALDI-TIMS overlapped with the ovarian epithelial carcinoma as identified by H & E staining and histological scoring. Furthermore, the structures for the most prevalent species observed via MALDI-TIMS (d18:1/C16:0-, d18:1/C24:1- and d18:1/C24:0-ST) were confirmed by MALDI-TIMS/MS, whereas, a neighboring ion(m/z 885.6) that was not tumor specific was identified as a phosphatidylinositol. Microarray analysis of mRNAs collected using laser capture microdissection revealed that expression of GalCer synthase and Gal3ST1 (3'-phosphoadenosine-5'-phosphosulfate:GalCer sulfotransferase) were approximately 11- and 3.5-fold higher, respectively, in the ovarian epithelial carcinoma cells versus normal ovarian stromal tissue, and they were 5- and 2.3-fold higher in comparison with normal surface ovarian epithelial cells, which is a likely explanation for the higher ST. CONCLUSIONS: This study combined transcriptomic and lipidomic approaches to establish that sulfatides are elevated in ovarian cancer and should be evaluated further as factors that might be important in ovarian cancer biology and, possibly, as biomarkers.
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181
Harris, J. F.; Beaton, D. W. Clin. Exp. Metastasis 1990, 8, 361
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Sulfated glycoconjugate determinants recognized by monoclonal antibody, SG-1, correlate with the experimental metastatic ability of KHT fibrosarcoma cells
Harris, J. F.; Beaton, D. W.
Clinical & Experimental Metastasis (1990), 8 (4), 361-79CODEN: CEXMD2; ISSN:0262-0898.
The binding and functional activity was examd. of monoclonal antibody (MAb) SG-1 that was raised by immunization against embryonal carcinoma cells and screened using KHT fibrosarcoma cells. Quant. absorption, binding and in situ immunochem. staining assays indicate that the MAb SG-1-defined epitopes are expressed preferentially by the highly metastatic KHT35-L1 cells relative to the weakly metastatic, parental KHTp cells. Furthermore, there was a significant correlation between the expression of MAb SG-1-defined antigen on the cells, following trypsin treatment, and their metastatic ability. Binding of MAb SG-1 to antigen was inhibited by specific sulfated polysaccharides including cerebroside sulfate (brain sulfatide), fucoidan, and dextran sulfate (500 kD) but not by heparin, chondroitin, keratan, or dextran (5 kD) sulfates. Initial characterization of antigen from KHT cells indicates that the epitope of MAb SG-1 is defined by sulfated glycoconjugates contg. galactose and sulfate but not N-acetylglucosamine. In the total lipid exts. of KHT35-L1 cells the antigen was detected in the delipidated protein fraction as well as in the chloroform/methanol fraction. Thus, the sulfated glycoconjugate determinants identified by MAb SG-1 may be relevant to the metastatic process of KHT fibrosarcoma cells.
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Iwabuchi, K.; Nagaoka, I. Blood 2002, 100, 1454
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Chatterjee, S.; Pandey, A. Biochim. Biophys. Acta 2008, 1780, 370
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184
Won, J. S.; Singh, A. K.; Singh, I. J. Neurochem. 2007, 103 (Suppl 1) 180
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Lactosylceramide: a lipid second messenger in neuroinflammatory disease
Won, Je-Seong; Singh, Avtar K.; Singh, Inderjit
Journal of Neurochemistry (2007), 103 (Suppl. 1), 180-191CODEN: JONRA9; ISSN:0022-3042. (Blackwell Publishing Ltd.)
A review. Inflammatory disease plays a crit. role in the pathogenesis of many neurol. disorders. Astrogliosis and induction of pro-inflammatory mediators such as chemokines, cytokines and inducible nitric oxide synthase (iNOS) are the 'hallmarks' of inflammatory disease. Increased activity of lactosylceramide (LacCer) synthase and increased synthesis of LacCer during glial proliferation, and induction of pro-inflammatory cytokines and iNOS suggests a role for LacCer in these cellular signaling pathways. Studies using complementary techniques of inhibitors and antisense reported that inhibition of LacCer synthesis inhibits glial proliferation, as well as the induction of pro-inflammatory mediators (cytokines and iNOS). This inhibition was bypassed by exogenous LacCer, but not by other related lipids (e.g. glucosylceramide, galactocerebroside, GD1, GM1), indicating a role for LacCer in inflammatory signaling pathways. Furthermore, inhibition of glial proliferation and induction of inflammatory mediators by antisense to Ras GTPase, PI3-Kinase and inhibitors of mitogen-activated protein kinase indicate the participation of the phosphoinositide 3-kinase (PI3Kinas)/Ras/mitogen-activated protein kinase/nuclear factor-κB (NF-κB) signaling pathways in LacCer-mediated inflammatory events thus exposing addnl. targets for therapeutics for inflammatory disease conditions.
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Nakayama, H.; Yoshizaki, F.; Prinetti, A.; Sonnino, S.; Mauri, L.; Takamori, K.; Ogawa, H.; Iwabuchi, K. J. Leukocyte Biol. 2008, 83, 728
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185
Lyn-coupled LacCer-enriched lipid rafts are required for CD11b/CD18-mediated neutrophil phagocytosis of nonopsonized microorganisms
Nakayama, Hitoshi; Yoshizaki, Fumiko; Prinetti, Alessandro; Sonnino, Sandro; Mauri, Laura; Takamori, Kenji; Ogawa, Hideoki; Iwabuchi, Kazuhisa
Journal of Leukocyte Biology (2008), 83 (3), 728-741CODEN: JLBIE7; ISSN:0741-5400. (Federation of American Societies for Experimental Biology)
The integrin CD11b/CD18 plays a central role in neutrophil phagocytosis. Although CD11b/CD18 binds a wide range of ligands, including C3bi and β-glucan, and transmits outside-in signaling, the mechanism of this signaling responsible for phagocytosis remains obscure. Here, we report that lactosylceramide (LacCer)-enriched lipid rafts are required for CD11b/CD18-mediated phagocytosis of nonopsonized zymosans (NOZs) by human neutrophils. Anti-CD11b and anti-LacCer antibodies inhibited the binding of NOZs to neutrophils and the phagocytosis of NOZs. During phagocytosis of NOZ, CD11b and LacCer were accumulated and colocalized in the actin-enriched phagocytic cup regions. Immunopptn. expts. suggested that CD11b/CD18 was mobilized into the LacCer-enriched lipid rafts during phagocytosis of NOZs. DMSO-treated, neutrophil-like HL-60 cells (D-HL-60 cells) lacking Lyn-coupled, LacCer-mediated signaling showed little phagocytosis of NOZs. However, loading of D-HL-60 cells with C24 fatty acid chain-contg. LacCer (C24-LacCer) reconstructed functional Lyn-assocd., LacCer-enriched lipid rafts, and restored D-HL-60 cell NOZ phagocytic activity, which was inhibited by anti-LacCer and anti-CD11b antibodies. Lyn knockdown by small interfering RNA blocked the effect of C24:1-LacCer loading on D-HL-60 cell phagocytosis of NOZs. CD11b/CD18 activation expts. indicated phosphorylation of LacCer-assocd. Lyn by activation of CD11b. Taken together, these observations suggest that CD11b activation causes translocation of CD11b/CD18 into Lyn-coupled, LacCer-enriched lipid rafts, allowing neutrophils to phagocytose NOZs via CD11b/CD18.
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Role of very long fatty acid-containing glycosphingolipids in membrane organization and cell signaling: The model of lactosylceramide in neutrophils
Sonnino, Sandro; Prinetti, Alessandro; Nakayama, Hitoshi; Yangida, Mitsuaki; Ogawa, Hideoki; Iwabuchi, Kazuhisa
Glycoconjugate Journal (2009), 26 (6), 615-621CODEN: GLJOEW; ISSN:0282-0080. (Springer)
A review. Glycosphingolipids are highly enriched in specialized membrane microdomains ("lipid rafts", caveolar domains and glycosynapses), and they participate to the process of transduction of information across the membrane. Lactosylceramide (LacCer) is specifically coupled with the Src family kinase Lyn in plasma membrane microdomains of human neutrophils. Ligand binding to LacCer activates Lyn, resulting in neutrophil functions, such as superoxide generation and migration. The β-Gal-(1-4)-β-Glc disaccharide structure of LacCer is necessary, but it is not sufficient for LacCer-mediated Lyn activation. For this function, the presence of a LacCer mol. species with ceramide contg. a very long fatty acid chain is also required. In this manuscript, the authors discuss the importance of interdigitation within the membrane, promoted by the presence of glycosphingolipid species with very long fatty acyl chains as determinants for membrane organization, instrumental to the signaling process.
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198
Falguieres, T.; Maak, M.; von Weyhern, C.; Sarr, M.; Sastre, X.; Poupon, M. F.; Robine, S.; Johannes, L.; Janssen, K. P. Mol. Cancer Ther. 2008, 7, 2498
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Human colorectal tumors and metastases express Gb3 and can be targeted by an intestinal pathogen-based delivery tool
Falguieres, Thomas; Maak, Matthias; von Weyhern, Claus; Sarr, Marianne; Sastre, Xavier; Poupon, Marie-France; Robine, Sylvie; Johannes, Ludger; Janssen, Klaus-Peter
Molecular Cancer Therapeutics (2008), 7 (8), 2498-2508CODEN: MCTOCF; ISSN:1535-7163. (American Association for Cancer Research)
The targeting of solid tumors requires delivery tools that resist intracellular and extracellular inactivation, and that are taken up specifically by tumor cells. We have shown previously that the recombinant nontoxic B-subunit of Shiga toxin (STxB) can serve as a delivery tool to target digestive tumors in animal models. The aim of this study was to expand these expts. to human colorectal cancer. Tissue samples of normal colon, benign adenomas, colorectal carcinomas, and liver metastases from 111 patients were obtained for the quantification of the expression of the cellular STxB receptor, the glycosphingolipid globotriaosyl ceramide (Gb3 or CD77). We found that compared with normal tissue, the expression of Gb3 was strongly increased in colorectal adenocarcinomas and their metastases, but not in benign adenomas. Short-term primary cultures were prepd. from samples of 43 patients, and STxB uptake was studied by immunofluorescence microscopy. Of a given tumor sample, on av., 80% of the cells could visibly bind STxB, and upon incubation at 37°C, STxB was transported to the Golgi app., following the retrograde route. This STxB-specific intracellular targeting allows the mol. to avoid recycling and degrdn., and STxB could consequently be detected on tumor cells even 5 days after initial uptake. In conclusion, the targeting properties of STxB could be diverted for the delivery of contrast agents to human colorectal tumors and their metastases, whose early detection and specific targeting remains one of the principal challenges in oncol.
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199
Johannes, L.; Romer, W. Nat. Rev. Microbiol. 2010, 8, 105
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Shiga toxins: From cell biology to biomedical applications
Johannes, Ludger; Romer, Winfried
Nature Reviews Microbiology (2010), 8 (2), 105-116CODEN: NRMACK; ISSN:1740-1526. (Nature Publishing Group)
A review. Shiga toxin-producing Escherichia coli is an emergent pathogen that can induce hemolytic uremic syndrome. The toxin has received considerable attention not only from microbiologists but also in the field of cell biol., where it has become a powerful tool to study intracellular trafficking. In this Review, we summarize the Shiga toxin family members and their structures, receptors, trafficking pathways and cellular targets. We discuss how Shiga toxin affects cells not only by inhibiting protein biosynthesis but also through the induction of signalling cascades that lead to apoptosis. Finally, we discuss how Shiga toxins might be exploited in cancer therapy and immunotherapy.
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Engedal, N.; Skotland, T.; Torgersen, M. L.; Sandvig, K. Microb. Biotechnol. 2011, 4, 32
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Shiga toxin and its use in targeted cancer therapy and imaging
Engedal, Nikolai; Skotland, Tore; Torgersen, Maria L.; Sandvig, Kirsten
Microbial Biotechnology (2010), 4 (1), 32-46CODEN: MBIIB2; ISSN:1751-7915. (Wiley-Blackwell)
A review. Shiga and the Shiga-like toxins are related protein toxins produced by Shigella dysenteriae and certain strains of Escherichia coli. These toxins are composed of two non-covalently attached, modular parts: the A moiety (StxA) contg. the enzymically active A1 fragment, and the non-toxic, pentameric binding moiety (StxB). Stx binds specifically to the glycosphingolipid globotriaosylceramide (Gb3) at the surface of target cells and is then internalized by endocytosis. Subsequently, in toxin-sensitive cells, the Stx/Gb3 complex is transported in a retrograde manner via the Golgi app. to the endoplasmic reticulum, where the enzymically active part of Stx is translocated to the cytosol, enabling it to irreversibly inhibit protein synthesis via modification of ribosomal 28S RNA. Whereas Gb3 shows a relatively restricted expression in normal human tissues, it has been reported to be highly expressed in many types of cancers. This review gives a brief introduction to Stx and its intracellular transport. Furthermore, after a description of Gb3 and the methods that are currently used to detect its cellular expression, we provide an updated overview of the published reports on Gb3 overexpression in human cancers. Finally, we discuss the possibility of utilizing Stx or StxB coupled to therapeutic compds. or contrast agents in targeted cancer therapy and imaging.
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Christiansen, D.; Milland, J.; Mouhtouris, E.; Vaughan, H.; Pellicci, D. G.; McConville, M. J.; Godfrey, D. I.; Sandrin, M. S. PLoS Biol. 2008, 6, e172
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Kuan, C. T.; Chang, J.; Mansson, J. E.; Li, J.; Pegram, C.; Fredman, P.; McLendon, R. E.; Bigner, D. D. BMC Dev. Biol. 2010, 10, 114
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Westerlund, B.; Slotte, J. P. Biochim. Biophys. Acta 2009, 1788, 194
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Wennekes, T.; van den Berg, R. J.; Boot, R. G.; van der Marel, G. A.; Overkleeft, H. S.; Aerts, J. M. Angew. Chem., Int. Ed. Engl. 2009, 48, 8848
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Degroote, S.; Wolthoorn, J.; van Meer, G. Semin. Cell Dev. Biol. 2004, 15, 375
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The cell biology of glycosphingolipids
Degroote, Sophie; Wolthoorn, Jasja; Van Meer, Gerrit
Seminars in Cell & Developmental Biology (2004), 15 (4), 375-387CODEN: SCDBFX; ISSN:1084-9521. (Elsevier Science B.V.)
A review. Glycosphingolipids, a family of heterogeneous lipids with biophys. properties conserved from fungi to mammals, are key components of cellular membranes. Because of their tightly packed backbone, they have the ability to assoc. with other sphingolipids and cholesterol to form microdomains called lipid rafts, with which a variety of proteins assoc. These microdomains are thought to originate in the Golgi app., where most sphingolipids are synthesized, and are enriched at the plasma membrane. They are involved in an increasing no. of processes, including sorting of proteins by allowing selectivity in intracellular membrane transport. Apart from being involved in recognition and signaling on the cell surface, glycosphingolipids may fulfill unexpected roles on the cytosolic surface of cellular membranes.
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Ledeen, R. W.; Wu, G. Biochim. Biophys. Acta 2006, 1761, 588
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Dyatlovitskaya, E. V. Biochemistry (Moscow) 2007, 72, 479
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The role of lysosphingolipids in the regulation of biological processes
Dyatlovitskaya, E. V.
Biochemistry (Moscow) (2007), 72 (5), 479-484CODEN: BIORAK; ISSN:0006-2979. (Pleiades Publishing, Ltd.)
A review. This review summarizes data on the role of lysosphingolipids (glucosyl-and galactosylsphingosines, sphingosine-1-phosphate, sphingosine-1-phosphocholine) in the regulation of various biol. processes in normal and pathol. states.
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Meyer zu Heringdorf, D.; Jakobs, K. H. Biochim. Biophys. Acta 2007, 1768, 923
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Nixon, G. F.; Mathieson, F. A.; Hunter, I. Prog. Lipid Res. 2008, 47, 62
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The multi-functional role of sphingosylphosphorylcholine
Nixon, Graeme F.; Mathieson, Fiona A.; Hunter, Irene
Progress in Lipid Research (2008), 47 (1), 62-75CODEN: PLIRDW; ISSN:0163-7827. (Elsevier B.V.)
A review. The sphingomyelin metabolite, sphingosylphosphorylcholine (SPC) has been the subject of much recent interest and controversy. Studies have indicated that SPC naturally occurs in plasma and a constituent of lipoproteins. Synthesis is also increased in some pathol. conditions. Research has demonstrated that SPC is a potentially important lipid mediator of cell type specific functions in major tissues, such as heart, blood vessels, skin, brain and immune system. These effects are regulated via a no. of different intracellular signalling cascades, also dependent upon cell type. Initial reports identifying high affinity SPC receptors at first appeared to reinforce the physiol. relevance of this sphingolipid. However, these studies have now been retracted. Some SPC effects have been shown be occur via plasma membrane receptors for the related sphingolipid, sphingosine 1-phosphate (S1P). Despite a lack of well-defined receptor signal transduction mechanisms and sparse pharmacol. data, several key characteristics of SPC are now emerging. SPC can act as a mitogen in several different cell types and in certain circumstances, may also be a pro-inflammatory mediator. In this review, these actions of SPC are discussed with a view to understanding the potential physiol. relevance of this sphingolipid.
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Okamoto, R.; Arikawa, J.; Ishibashi, M.; Kawashima, M.; Takagi, Y.; Imokawa, G. J. Lipid Res. 2003, 44, 93
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Imokawa, G. J. Dermatol. Sci. 2009, 55, 1
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A possible mechanism underlying the ceramide deficiency in atopic dermatitis: Expression of a deacylase enzyme that cleaves the N-acyl linkage of sphingomyelin and glucosylceramide
Imokawa, Genji
Journal of Dermatological Science (2009), 55 (1), 1-9CODEN: JDSCEI; ISSN:0923-1811. (Elsevier Ireland Ltd.)
A review. A deficiency of ordinary ceramides in the stratum corneum is an essential etiol. factor for the dry and barrier-disrupted skin of patients with atopic dermatitis (AD). We have proposed that the mechanism underlying that deficiency involves a novel sphingolipid metabolizing enzyme, termed sphingomyelin (SM) glucosylceramide (GCer) deacylase, which hydrolyzes SM or GCer at the acyl site to yield their lysoforms sphingosylphosphorylcholine (SPC) or glucosylsphingosine (GSP) instead of ceramide, leading to the ceramide deficiency in the AD skin. The enzymic characteristics obsd. showed a pH dependency of catalytic activity with a peak at pH 5.0 and a mol. wt. of 40,000. Anal. isoelec. focusing (IEF) chromatog. demonstrated that the pI values of SM deacylase, GlcCDase, SMase and ceramidase were 4.2, 7.4, 7.0 and 5.7, resp. Those enzymic characteristics of SM-GCer deacylase are completely distinct from ceramidase as well as the other known deacylases. Our enzymic measurements demonstrated that SM-GCer deacylase activity is enhanced more than 5-fold in involved stratum corneum, more than 3-fold in uninvolved stratum corneum and approx. 3-fold in the involved epidermis from patients with AD compared with healthy controls. Our findings suggest that the novel enzyme, SM-GCer deacylase, is expressed in situ at significant levels in the epidermis of AD patients. This results in the prodn. of SPC and GSP, instead of ceramides, which leads in turn to the ceramide deficiency seen in the stratum corneum of those patients. It is likely that the biogenesis of SM-GCer deacylase may be crit. to the pathogenesis of AD.
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Twenty five years of the "psychosine hypothesis": a personal perspective of its history and present status
Suzuki, Kunihiko
Neurochemical Research (1998), 23 (3), 251-259CODEN: NEREDZ; ISSN:0364-3190. (Plenum Publishing Corp.)
A review, with 54 refs. Twenty five years ago in 1972, a hypothesis was introduced to explain the pathogenetic mechanism underlying the unusual cellular and biochem. characteristics of globoid cell leukodystrophy (Krabbe disease). It postulated that galactosylsphingosine (psychosine), which cannot be degraded due to the underlying genetic defect, is responsible for the very rapid loss of the oligodendrocytes and the consequent paradoxical anal. finding, the lack of accumulation of the primary substrate, galactosylceramide, in patients' brain. It took nearly ten years before the actual accumulation of psychosine was demonstrated in human Krabbe patients and also in the brain of twitcher mice, an equiv. murine mutant. Meanwhile this "psychosine hypothesis" has been extended to Gaucher disease and then to a more general hypothesis encompassing all sphingolipidoses that the "lyso-derivs." of the primary sphingolipid substrates of the defective enzymes in resp. disorders play a key role in their pathogenesis. Some of these extensions not only remain speculative without conclusive factual evidence but may eventually turn out to be an overstretching. This article attempts, from my personal perspective, at tracing historical development of the "psychosine hypothesis" and examg. its current status and possible future directions.
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Carter, H. E.; Nalbandov, O.; Tavormina, P. A. J. Biol. Chem. 1951, 192, 197
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Kisic, A.; Tsuda, M.; Kulmacz, R. J.; Wilson, W. K.; Schroepfer, G. J., Jr. J. Lipid Res. 1995, 36, 787
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Igarashi, Y.; Hakomori, S. Biochem. Biophys. Res. Commun. 1989, 164, 1411
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Morales, P. R.; Dillehay, D. L.; Moody, S. J.; Pallas, D. C.; Pruett, S.; Allgood, J. C.; Symolon, H.; Merrill, A. H., Jr. Drug Chem. Toxicol. 2007, 30, 197
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Safingol toxicology after oral administration to TRAMP mice: demonstration of safingol uptake and metabolism by N-acylation and N-methylation
Morales, Pablo R.; Dillehay, Dirck L.; Moody, Steven J.; Pallas, David C.; Pruett, Sarah; Allgood, Jeremy C.; Symolon, Holly; Merrill, Alfred H., Jr.
Drug and Chemical Toxicology (1977) (2007), 30 (3), 197-216CODEN: DCTODJ; ISSN:0148-0545. (Informa Healthcare)
Safingol [(2S,3S)-2-amino-1,3-octadecanediol] is an unnatural L-threo-stereoisomer of sphinganine that is cytotoxic for cancer cells in culture and is being tested in phase 1 human clin. trials. To det. if safingol can be absorbed orally and if it affects prostate cancer in a mouse strain used in prostate cancer studies, safingol was fed to TRAMP (transgenic adenocarcinoma of mouse prostate) mice for 2 wk at 0.0125% to 0.1% wt./wt. of the diet. Anal. of safingol and safingol metabolites in blood and tissues by liq. chromatog. electrospray ionization tandem mass spectrometry revealed uptake in tissue and extensive conversion of safingol to N-acyl species (comparable to natural "ceramides") and mono-, di-, and tri-N-Me metabolites that have not been obsd. previously. Safingol caused significant hepatotoxicity at all dosages, as reflected in elevated liver alanine aminotransferase, and at the highest dose (0.1 %) caused changes in liver histol. (appearance of autophagosomal vacuoles) and renal toxicity (based on elevation of blood urea nitrogen) and decreases in packed blood cell vol. and body wt. Safingol did not inhibit the prostate pre-neoplastic lesion (prostate intraepithelial neoplasia) in TRAMP mice; however, addnl. studies at lower dosages for longer time were not pursued due to host toxicity. Safingol and its N-Me metabolites were cytotoxic to both a human prostate cell line (DU145) and mouse BALB 3T3 cells; therefore, the host and potential antitumor toxicity may be due to multiple mol. species of safingol.
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Doering, T.; Proia, R. L.; Sandhoff, K. FEBS Lett. 1999, 447, 167
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Stewart, M. E.; Downing, D. T. J. Lipid Res. 2001, 42, 1105
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Farwanah, H.; Pierstorff, B.; Schmelzer, C. E.; Raith, K.; Neubert, R. H.; Kolter, T.; Sandhoff, K. J. Chromatogr., B: Anal. Technol. Biomed. Life Sci. 2007, 852, 562
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Separation and mass spectrometric characterization of covalently bound skin ceramides using LC/APCI-MS and Nano-ESI-MS/MS
Farwanah, Hany; Pierstorff, Barbara; Schmelzer, Christian E. H.; Raith, Klaus; Neubert, Reinhard H. H.; Kolter, Thomas; Sandhoff, Konrad
Journal of Chromatography, B: Analytical Technologies in the Biomedical and Life Sciences (2007), 852 (1-2), 562-570CODEN: JCBAAI; ISSN:1570-0232. (Elsevier B.V.)
Ceramides covalently bound to keratinocytes are essential for the barrier function of the skin, which can be disturbed in diseases, such as psoriasis and atopic dermatitis. These ceramides of the classes ω-hydroxyacyl-sphingosine and ω-hydroxyacyl-6-hydroxysphingosine contain an ω-hydroxy fatty acid. For their sepn. and identification, a new anal. approach based on normal phase liq. chromatog. coupled to atm. pressure chem. ionization mass spectrometry and tandem nano-electrospray mass spectrometry, resp., is presented here. Tandem mass spectrometry provided structural information about the sphingoid base as well as the fatty acid moieties. The chain lengths of the bases ranged from C12 to C22, the chain lengths of the fatty acids varied between C28 and C36. In total, 67 ceramide species have been identified in human skin. The anal. methods presented in this work can be helpful for investigating alterations in the ceramide compn. of the skin as seen in psoriasis, atopic dermatitis, and diseases with impaired epidermal barrier function.
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Bosson, R.; Guillas, I.; Vionnet, C.; Roubaty, C.; Conzelmann, A. Eukaryot. Cell 2009, 8, 306
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Incorporation of ceramides into Saccharomyces cerevisiae glycosylphosphatidylinositol-anchored proteins can be monitored in vitro
Bosson, Regine; Guillas, Isabelle; Vionnet, Christine; Roubaty, Carole; Conzelmann, Andreas
Eukaryotic Cell (2009), 8 (3), 306-314CODEN: ECUEA2; ISSN:1535-9786. (American Society for Microbiology)
After glycosylphosphatidylinositols (GPIs) are added to GPI proteins of Saccharomyces cerevisiae, a fatty acid of the diacylglycerol moiety is exchanged for a C26:0 fatty acid through the subsequent actions of Per1 and Gup1. In most GPI anchors this modified diacylglycerol-based anchor is subsequently transformed into a ceramide-contg. anchor, a reaction which requires Cwh43. Here we show that the last step of this GPI anchor lipid remodeling can be monitored in microsomes. The assay uses microsomes from cells that have been grown in the presence of myriocin, a compd. that blocks the biosynthesis of dihydrosphingosine (DHS) and thus inhibits the biosynthesis of ceramide-based anchors. Such microsomes, when incubated with [3H]DHS, generate radiolabeled, ceramide-contg. anchor lipids of the same structure as made by intact cells. Microsomes from cwh43Δ or mcd4Δ mutants, which are unable to make ceramide-based anchors in vivo, do not incorporate [3H]DHS into anchors in vitro. Moreover, gup1Δ microsomes incorporate [3H]DHS into the same abnormal anchor lipids as gup1Δ cells synthesize in vivo. Thus, the in vitro assay of ceramide incorporation into GPI anchors faithfully reproduces the events that occur in mutant cells. Incorporation of [3H]DHS into GPI proteins is obsd. with microsomes alone, but the reaction is stimulated by cytosol or bovine serum albumin, ATP plus CoA, or C26:0-CoA, particularly if microsomes are depleted of acyl-CoA. Thus, [3H]DHS cannot be incorporated into proteins in the absence of acyl-CoA.
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Sphingolipid long-chain-base auxotrophs of Saccharomyces cerevisiae: genetics, physiology, and a method for their selection
Pinto, William J.; Srinivasan, Bharath; Shepherd, Sherri; Schmidt, Ann; Dickson, Robert C.; Lester, Robert L.
Journal of Bacteriology (1992), 174 (8), 2565-74CODEN: JOBAAY; ISSN:0021-9193.
A selection method for sphingolipid long-chain-base auxotrophs of S. cerevisiae was devised after observing that strains that require a long-chain base for growth become denser when starved for this substance. Genetic anal. of >60 such strains indicated only 2 complementation classes, lcb1 and lcb2. Mutant strains from each class grew equally well with 3-ketodihydrophingosine, erythrodihydrosphingosine or threodihydrosphingosine, or phytosphingosine. Since these metabolites represent the first, second, and last components, resp., of the long-chain-base biosynthetic pathway, it is likely that the LCB1 and LCB2 genes are involved in the first step of long-chain-based synthesis. The results of long-chain-base starvation in the Lcb- strains suggest that ≥1 sphingolipids have a vital role in S. cerevisiae. Immediate sequelae of long-chain-base starvation were loss of viability, exacerbated in the presence of α-cyclodextrin, and loss of phosphoinositol sphingolipid synthesis but not phosphatidylinositol synthesis. Loss of viability with long-chain-base starvation could be prevented by also blocking either protein or nucleic acid synthesis. Without a long-chain-base, cell division, dry mass accumulation, and protein synthesis continued at a diminished rate and were further inhibited by the detergent Tergitol. The cell d. increase induced by long-chain-base starvation is thus explained as a differential loss of cell division and mass accumulation. Long-chain-base starvation in Lcb- S. cerevisiae and inositol starvation of Inos- S. cerevisiae share common features: an increase in cell d. and a loss of cell viability overcome by blocking macromol. synthesis.
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Adachi-Yamada, T.; Gotoh, T.; Sugimura, I.; Tateno, M.; Nishida, Y.; Onuki, T.; Date, H. Mol. Cell. Biol. 1999, 19, 7276
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De novo synthesis of sphingolipids is required for cell survival by down-regulating c-Jun N-terminal kinase in Drosophila imaginal discs
Adachi-Yamada, Takashi; Gotoh, Tomokazu; Sugimura, Isamu; Tateno, Minoru; Nishida, Yasuyoshi; Onuki, Tomoya; Date, Hideyuki
Molecular and Cellular Biology (1999), 19 (10), 7276-7286CODEN: MCEBD4; ISSN:0270-7306. (American Society for Microbiology)
Mitogen-activated protein kinase (MAPK) is a conserved eukaryotic signaling factor that mediates various signals, cumulating in the activation of transcription factors. Extracellular signal-regulated kinase (ERK), a MAPK, is activated through phosphorylation by the kinase MAPK/ERK kinase (MEK). To elucidate the extent of the involvement of ERK in various aspects of animal development, we searched for a Drosophila mutant which responds to elevated MEK activity and herein identified a lace mutant. Mutants with mild lace alleles grow to become adults with multiple aberrant morphologies in the appendages, compd. eye, and bristles. These aberrations were suppressed by elevated MEK activity. Structural and transgenic analyses of the lace cDNA have revealed that the lace gene product is a membrane protein similar to the yeast protein LCB2, a subunit of serine palmitoyltransferase (SPT), which catalyzes the 1st step of sphingolipid biosynthesis. In fact, SPT activity in the fly expressing epitope-tagged Lace was absorbed by epitope-specific antibody. The no. of dead cells in various imaginal disks of a lace hypomorph was considerably increased, thereby ectopically activating c-Jun N-terminal kinase (JNK), another MAPK. These results account for the adult phenotypes of the lace mutant and suppression of the phenotypes by elevated MEK activity: we hypothesize that mutation of lace causes decreased de novo synthesis of sphingolipid metabolites, some of which are signaling mols., and ≥1 of these changes activates JNK to elicit apoptosis. The ERK pathway may be antagonistic to the JNK pathway in the control of cell survival.
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Schmelz, E. M.; Crall, K. J.; Larocque, R.; Dillehay, D. L.; Merrill, A. H., Jr. J. Nutr. 1994, 124, 702
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Schmelz, Eva Maria; Crall, Kara J.; Larocque, Regina; Dillehay, Dirck L.; Merrill, Alfred H., Jr.
Journal of Nutrition (1994), 124 (5), 702-12CODEN: JONUAI; ISSN:0022-3166.
In this study, radiolabeled sphingolipids were placed in isolated intestinal segments of female CF1 mice, and the metab. and distribution of the radiolabel were followed. Most of the sphingomyelin was degraded to ceramide and other products in all regions of the intestine, and increasing amts. of several [3H]-labeled sphingolipids appeared in the tissues. The results establish that some of the sphingomyelin that enters the gastrointestinal tract is hydrolyzed and taken up by the intestine, with the lipid backbone being degraded or reutilized for complex sphingolipid synthesis; however, at least a portion passes into the large intestine. The appearance of bioactive compds. throughout the gastrointestinal tract may alter the behavior of intestinal cells.
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Sphingolipids in food and the emerging importance of sphingolipids to nutrition
Vesper, Hubert; Schmelz, Eva-Maria; Nikolova-Karakashian, Mariana N.; Dillehay, Dirck L.; Lynch, Daniel V.; Merrill, Alfred H., Jr.
Journal of Nutrition (1999), 129 (7), 1239-1250CODEN: JONUAI; ISSN:0022-3166. (American Society for Nutritional Sciences)
A review with 181 refs. Eukaryotes and some prokaryotes and viruses contain sphingolipids defined by common backbone sphingoid base, such as sphingosine. The sphingolipids of mammalian tissues, lipoproteins, and milk include ceramides, sphingomyelins, cerebrosides, gangliosides, and sulfatides; plants, fungi, and yeast have mainly cerebrosides and phosphoinositides. The total amts. of sphingolipids in foods vary considerably, from a few micromoles per kg in fruits to several millimoles per kg in dairy products, eggs, and soybeans. The per capita sphingolipid consumption in the US is estd. at 150-180 mmol (∼115-140 g) per yr, or 0.3-0.4 g/day. There is no known nutritional requirement for sphingolipids, but they are hydrolyzed in the gastrointestinal tract to the same metabolites (ceramides and sphingoid bases) that are used by cells to regulate growth, differentiation, apoptosis, and other cellular functions. Studies in exptl. animals have shown that feeding sphingolipids inhibits colon carcinogenesis, decreases blood serum LDL cholesterol and elevates HDL, suggesting that sphingolipids may be a functional food constituent. Sphingolipid metab. can also be modified by dietary constituents, such as cholesterol, fatty acids, and mycotoxins (fumonisins), with consequences for cell regulation and disease. Assocns. among diet, sphingolipids, and health may emerge as more is learned about these compds.
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Dietary sphingomyelin inhibits 1,2-dimethylhydrazine-induced colon cancer in CF1 mice
Dillehay, Dirck L.; Webb, Sonji K.; Schmelz, Eva Maria; Merrill, Alfred H., Jr.
Journal of Nutrition (1994), 124 (5), 615-20CODEN: JONUAI; ISSN:0022-3166.
Sphingolipids are in all eukaryotic cells and modulate cell growth, differentiation, and transformation; however, little is known about the physiol. effects of their consumption. Mice were fed diets supplemented with milk sphingomyelin to det. effects on colon carcinogenesis. Cancer was initiated in CF1 mice by 1,2-dimethylhydrazine. Mice were then fed AIN76A diets supplemented with 0.025-0.1 g sphingomyelin/100 g for 28 wk until the supply of sphingomyelin was depleted and then fed unsupplemented diet for 24 wk. Sphingomyelin did not affect wt. gain. Mice fed sphingomyelin had a 20% incidence of colon tumors compared with 47% in controls. Tumors were adenomas or adenocarcinomas and located in the distal third of the colon. In shorter-term studies, colonic epithelial cell proliferation was significantly greater than controls in mice fed 0.025 g sphingomyelin/100 g diet, but not in those fed higher amts. of sphingomyelin. The no. of aberrant crypts was significantly lower in 1,2-dimethylhydrazine-treated mice fed 0.05 g sphingomyelin/100 g diet than in controls. These results demonstrate that consumption of sphingomyelin affects the behavior of colonic cells. Because sphingolipids are present in food, the redn. in 1,2-dimethylhydrazine-induced premalignant lesions and the incidence of colon tumors in CF1 mice implies that these compds. may be another important class of nutritional modulators of carcinogenesis.
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Schmelz, E. M.; Roberts, P. C.; Kustin, E. M.; Lemonnier, L. A.; Sullards, M. C.; Dillehay, D. L.; Merrill, A. H., Jr. Cancer Res. 2001, 61, 6723
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Symolon, H.; Schmelz, E. M.; Dillehay, D. L.; Merrill, A. H., Jr. J. Nutr. 2004, 134, 1157
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Dietary soy sphingolipids suppress tumorigenesis and gene expression in 1,2-dimethylhydrazine-treated CF1 mice and ApcMin/+ mice
Symolon, Holly; Schmelz, Eva M.; Dillehay, Dirck L.; Merrill, Alfred H., Jr.
Journal of Nutrition (2004), 134 (5), 1157-1161CODEN: JONUAI; ISSN:0022-3166. (American Society for Nutritional Sciences)
Dietary supplementation with milk sphingolipids inhibits colon tumorigenesis in CF1 mice treated with a colon carcinogen [1,2-dimethylhydrazine (DMH)] and in multiple intestinal neoplasia (Min) mice, which develop intestinal tumors spontaneously. Plant sphingolipids differ structurally from those of mammals [soy glucosylceramide (GlcCer) consists predominantly of a 4,8-sphingadiene backbone and α-hydroxy-palmitic acid], which might affect their bioactivity. Soy GlcCer was added to the AIN-76A diet (which contains <0.005% sphingolipid) to investigate whether it would also suppress tumorigenesis in these mouse models. Soy GlcCer reduced colonic cell proliferation in the upper half of the crypts in mice treated with DMH by 50 and 56% (P < 0.05) at 0.025 and 0.1% of the diet (wt/wt), resp., and reduced the no. of aberrant colonic crypt foci (an early marker of colon carcinogenesis) by 38 and 52% (P < 0.05). Min mice fed diets contg. 0.025 and 0.1% (wt/wt) soy GlcCer developed 22 and 37% fewer adenomas (P < 0.05), resp. The effects of dietary sphingolipids on gene expression in the intestinal mucosal cells of Min mice were analyzed using Affymetrix GeneChip microarrays. Soy GlcCer affected the expression of 96 genes by ≥2-fold in a dose-dependent manner, increasing 32 and decreasing 64. Decreases in the mRNA expression of 2 transcription factors assocd. with cancer, hypoxia-induced factor 1α (HIF1α) and transcription factor 4 (TCF4), were confirmed by quant. RT-PCR. In conclusion, soy GlcCer suppressed colon tumorigenesis in 2 mouse models; hence, plant sphingolipids warrant further investigation as inhibitors of colon cancer. Because soy contains relatively high amts. of GlcCer, sphingolipids may partially account for the anticancer benefits attributed to soy-based foods.
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Inamine, M.; Suzui, M.; Morioka, T.; Kinjo, T.; Kaneshiro, T.; Sugishita, T.; Okada, T.; Yoshimi, N. Cancer Sci. 2005, 96, 876
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Inamine, Morihiko; Suzui, Masumi; Morioka, Takamitsu; Kinjo, Tatsuya; Kaneshiro, Tatsuya; Sugishita, Tomoko; Okada, Tadashi; Yoshimi, Naoki
Cancer Science (2005), 96 (12), 876-881CODEN: CSACCM; ISSN:1347-9032. (Blackwell Publishing Asia Pty Ltd.)
Sphingolipids display a wide spectrum of biol. activities, including cell growth, differentiation and apoptosis. However, precise mechanisms by which these compds. exert anticancer or cancer-preventive effects are not known. In the present study, we evaluated the preventive efficacy of enriched dietary monoglucosylceramide 1-O-β-glucosyl-N-2'-hydroxyarachidoyl-4,8-sphingadienine (G1CM) on 1,2-dimethylhydrazine (DMH)-induced aberrant crypt foci (ACF) and β-catenin-accumulated crypt (BCAC) formation in F344 rats during initiation stage. We also examd. whether G1CM affects cell proliferation and apoptosis in these lesions. Pure G1CM was isolated from rice bran. Forty-two rats were divided randomly into five exptl. groups. Rats in groups 1-3 were given s.c. injections of DMH (40 mg/kg body wt.) once a week for 2 wk. One week before the first injection of DMH, rats in groups 2 and 3 were fed a diet contg. 200 and 1000 ppm G1CM, resp., for 5 wk. Rats in group 4 were fed a diet contg. 1000 ppm G1CM. Rats in group 5 were given the basal diet alone and served as untreated controls. The expt. was terminated 5 wk after the start. Dietary G1CM at both doses (groups 2 and 3) significantly inhibited the induction of ACF and BCAC (P < 0.001) when compared to group 1 treated with DMH alone. In groups 2 and 3, the proliferating cell nuclear antigen labeling indexes of epithelial cells in ACF and BCAC were also lower than in group 1 (P < 0.0001 for ACF, P < 0.05 for BCAC). These results, that dietary G1CM has possible chemopreventive effects in the present short-term colon carcinogenesis bioassays, suggest that longer exposure may cause suppression of tumor development.
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Simon, Kirk W.; Roberts, Paul C.; Vespremi, Michael J.; Manchen, Steven; Schmelz, Eva M.
Molecular Nutrition & Food Research (2009), 53 (3), 332-340CODEN: MNFRCV; ISSN:1613-4125. (Wiley-VCH Verlag GmbH & Co. KGaA)
Sphingolipid metabolites are generated throughout the intestinal tract after hydrolysis of orally administered complex sphingolipids and significantly suppress colon cancer in carcinogen-treated CF1 mice. In the present study, the mechanisms of tumor suppression by dietary sphingolipids were investigated. Changes in select genes that are crit. in early stages of colon cancer were analyzed in the colonic mucosa of dimethylhydrazine-treated CF1 mice fed AIN76A diet with or without 0.05% sphingomyelin (SM). Supplementation with SM did not significantly alter mRNA levels of most of the selected genes. However, a downregulation of β-catenin (p = 0.007) and increased protein levels of connexin-43 (p = 0.017) and Bcl-2 (p = 0.033) were obsd. in SM-fed animals. This suggests that sphingolipids may be regulating specific post-transcriptional events to reverse aberrant expression of individual proteins. Since the dysregulation of β-catenin metab. and its transcriptional activity in addn. to a decreased intercellular communication was causally linked to the development of colon cancer while a low Bcl-2 expression is assocd. with a worse prognosis in colon cancer, the reversal of these early changes may be important events in the prevention of colon cancer by orally administered sphingolipids, and may provide specific mol. biomarkers for sphingolipid efficacy in vivo.
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Fujiwara, K.; Kitatani, K.; Fukushima, K.; Yazama, H.; Umehara, H.; Kikuchi, M.; Igarashi, Y.; Kitano, H.; Okazaki, T. Int. J. Clin. Oncol. 2011, 16, 133
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Fujiwara, Kazunori; Kitatani, Kazuyuki; Fukushima, Kei; Yazama, Hiroaki; Umehara, Hisanori; Kikuchi, Mitsunori; Igarashi, Yasuyuki; Kitano, Hiroya; Okazaki, Toshiro
International Journal of Clinical Oncology (2011), 16 (2), 133-140CODEN: IJCOF6; ISSN:1341-9625. (Springer Japan)
Background: Sphingolipids, components of cellular membranes in eukaryotic cells, have roles in the regulation of tumor growth, inflammation, angiogenesis, and immunity. We investigated the effects of dietary glucosylceramides, sphingolipids isolated from rice bran, on tumor growth of human head and neck squamous cell carcinoma. Methods: The tumor cell line SCCKN cells isolated from well-differentiated human head and neck cancer were s.c. inoculated into the right flank of NOD/SCID mice, to establish an SCCKN xenograft model. Rice bran glucosylceramides (300 mg/kg/day) were administered orally to the mice for 14 consecutive days. Results: Dietary glucosylceramides significantly inhibited the growth of the xenograft tumor in comparison with the control group. The TUNEL stain revealed that treatment of mice with glucosylceramides increased the no. of apoptotic cells in the implanted tumor tissues and that apoptosis induction was accompanied by the formation of active/cleaved caspase-3. Conclusion: These results suggest that dietary glucosylceramides possibly exert anti-tumor activity by inducing apoptosis of head and neck squamous cell carcinoma. Therefore, their potential usefulness in treatment and prevention of human head and neck squamous cell carcinoma warrants further investigation.
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Journal of Bacteriology (1991), 173 (14), 4325-32CODEN: JOBAAY; ISSN:0021-9193.
The existence of auxotrophic mutants of S. cerevisiae having an abs. requirement for the long-chain base (lcb) component of sphingolipids suggests that sphingolipids are crucial for viability and growth. One mutant, termed the lcb1-1 mutant, lacks the activity of serine palmitoyltransferase, the first enzyme in the pathway for long-chain base synthesis. Here, an evidence is presented that LCB1 has been molecularly cloned. The size of the LCB1 transcript, the direction of transcription, the transcription initiation sites were detd. In addn., the coding region and its 5' and 3' flanking regions were sequenced. Anal. of the DNA sequence revealed a single open reading frame of 1674 nucleotides, encoding a predicted peptide of 558 amino acids. The hydropathy profile of the predicted peptide suggests a hydrophobic, globular, membrane-assocd. protein with two potential transmembrane helices. Comparison of the predicted amino acid sequence to known protein sequences revealed homol. to 5-aminolevulinic acid synthase and to 2-amino-3-ketobutyrate CoA ligase. These homologies, the similarity of the chem. reactions catalyzed by the 3 enzymes, and the finding that LCB1 restores serine palmitoyltransferase activity to an lcb1-defective strain indicate that serine palmitoyltransferase or a subunit of the enzyme is the most likely product of LCB1. Homol. of the LCB1 predicted protein to the Escherichia coli biotin synthetase was also obsd., but the biol. significance of this observation is not clear. A role for sphingolipid in sporulation is implicated by the finding that diploids homozygous for lch1 failed to sporulate.
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Serine palmitoyltransferase (SPT, EC 2.3.1.50) is the key enzyme in sphingolipid biosynthesis. It catalyzes the pyridoxal-5'-phosphate-dependent condensation of L-serine and palmitoyl-CoA to 3-oxosphinganine. Human expressed-sequence-tag (EST) clones are similar to the two yeast genes for synthesis of long-chain bases, LCB1 and LCB2, which are believed to encode two subunits of SPT [Buede, R., Pinto, W. J., Lester, R. L. & Dickson, R. C. (1991) J. Bacteriol. 173, 4325-5332; Nagiec, M. M., Baltisberger, J. A., Wells, G. B., Lester, R. L. & Dickson, R. C. (1994) Proc. Natl. Acad. Sci. USA 91, 7899-7902]. We have cloned and characterized two complete human and murine cDNA sequences named hLCB1 & mLCB1 and hLCB2 & mLCB2, resp., similar to the yeast LCB1 and LCB2 genes. Human embryonic kidney cells (HEK 293) transfected with murine sequences of LCB1 (mLCB1) and LCB2 (mLCB2) independently and in coexpression showed an overexpression of the transcripts on the mRNA and protein level. The enzymic activity of cells expressing mLCB2 alone or coexpressed with mLCB1 was three times higher than the activity of untransfected HEK cells. MLCB1 expression was not required for the synthesis of 3-oxo-sphinganine in mammalian cells. Transcription/translation in vitro yielded mLCB1 (53 kDa) and mLCB2 (63 kDa). The two proteins do not contain a signal peptide nor are they glycosylated. The endogenous and overexpressed SPT activity were both sensitive to common SPT inhibitors. Labeling studies with [1-14C]palmitic acid indicated that cell lines transfected with mLCB2 preferentially use the excess sphingoid bases for glucocerebroside and galactocerebroside synthesis. Our results provide conclusive genetic and biochem. evidence that the human and murine LCB2 genes described here encode serine palmitoyltransferase. Further studies will be required to unravel the function of the LCB1 gene in mammalian cells.
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Journal of Histochemistry and Cytochemistry (2003), 51 (6), 715-726CODEN: JHCYAS; ISSN:0022-1554. (Histochemical Society, Inc.)
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STEP 1:

STEP 2:

Sphingolipid and Glycosphingolipid Metabolic Pathways in the Era of SphingolipidomicsClick to copy article linkArticle link copied!

Chemical Reviews

SPECIAL ISSUE

Introduction

An Overview of Sphingolipid Structure and Function

Backbone and Headgroup Nomenclature

Figure 1

Figure 2

Figure 3

Variation in the Lipid Moieties

Sphingoid Base Diversity

N-Acyl-sphingoid Bases (Ceramides)

Variation of the Complex Sphingolipid Headgroups

Phosphosphingolipids

Glycosphingolipids

Other Types of Compounds

Sphingolipid Metabolic Pathways

Biosynthesis of the Lipid Moieties de Novo

Figure 4

Formation of the Sphingoid Base Backbones

Figure 5

Figure 6

Ceramide Synthases

Desaturation and Hydroxylation of Dihydroceramide to Form Ceramides and 4-Hydroxyceramides (Phytoceramides)

Complex Sphingolipid Biosynthesis

Figure 7

Sphingomyelin, Ceramide Phosphoethanolamine, and Ceramide Phosphate

Other Non-Glycan Headgroups

Glycosphingolipids

Biosynthesis of GlcCer

Biosynthesis of LacCer

Biosynthesis of Ganglio-Series Glycosphingolipids

Figure 8

Biosynthesis of Lacto-/Neolacto-Series Glycosphingolipids

Biosynthesis of Globo-/Isoglobo-Series Glycosphingolipids

Biosynthesis of GalCer

Sulfated Glycosphingolipids

Integration of Backbone and Headgroup Biosynthetic Pathways

Figure 9

Sphingolipid Turnover, Trafficking, and Recycling

Metabolic Turnover

Figure 10

Sphingolipid Trafficking and Membrane Dynamics

Figure 11

Sphingolipid Recycling (Salvage Pathways)

Analysis of Sphingolipid Metabolism by “Omic” Technologies

Use of Mass Spectrometry for Sphingolipidomics

Tissue-Imaging Mass Spectrometry of Sphingolipids

Integration of “Omic” Data Sets for a Systems Biology of Sphingolipid Metabolism and Function

Visualization Tools

Mathematical Modeling

Perspective on the Current State of Sphingolipid Research

Author Information

Biography

Alfred H. Merrill, Jr.

Acknowledgment

References

Sphingolipid and Glycosphingolipid Metabolic Pathways in the Era of Sphingolipidomics
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