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Alternatives to Nuclear Overhauser Enhancement Spectroscopy Presat and Carr–Purcell–Meiboom–Gill Presat for NMR-Based Metabolomics
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† ‡ § †Complex Carbohydrate Research Center (CCRC), ‡Departments of Genetics and Biochemistry & Molecular Biology, and §Institute of Bioinformatics, University of Georgia, 315 Riverbend Road, Athens, Georgia 30602, United States
*E-mail: [email protected]
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Analytical Chemistry

Cite this: Anal. Chem. 2017, 89, 17, 8582–8588
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https://doi.org/10.1021/acs.analchem.7b02354
Published July 24, 2017

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Abstract

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NMR metabolomics are primarily conducted with 1D nuclear Overhauser enhancement spectroscopy (NOESY) presat for water suppression and Carr–Purcell–Meiboom–Gill (CPMG) presat as a T2 filter to remove macromolecule signals. Others pulse sequences exist for these two objectives but are not often used in metabolomics studies, because they are less robust or unknown to the NMR metabolomics community. However, recent improvements on alternative pulse sequences provide attractive alternatives to 1D NOESY presat and CPMG presat. We focus this perspective on PURGE, a water suppression technique, and PROJECT presat, a T2 filter. These two pulse sequences, when optimized, performed at least on par with 1D NOESY presat and CPMG presat, if not better. These pulse sequences were tested on common samples for metabolomics, human plasma, and urine.

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NMR-based metabolomics has become established over the past 2 decades, with a great amount of work done to standardize the acquisition parameters and analysis of the data. (1-3) While 2D NMR metabolomics are sometimes used, (4-6) the majority of NMR-based metabolomics are conducted using 1D pulse sequences, with most of these studies relying on two pulse sequences: 1D nuclear Overhauser enhancement spectroscopy (NOESY) presat (7, 8) (solvent suppression) and Carr–Purcell–Meiboom–Gill (CPMG) presat (9, 10) (T2 filter).
Both pulse sequences have become gold standards for NMR-based metabolomics, thanks to their effectiveness at removing unwanted signals and general robustness. Despite their utility, these pulse sequences have limitations, as we will show below. For these cases, recently developed alternatives are worth considering.
For water suppression, several pulse sequences have been already designed, like presaturation, (11) composite pulses, (12) WET, (13, 14) WATERGATE, (15-18) or PURGE. (19) Despite all these variants, the 1D NOESY presat pulse sequence (noesypr1d on Bruker spectrometers) has emerged as the leading choice for NMR-based metabolomics. One of the main reasons for the success of noesypr1d is its ability to greatly suppress the water peak without intensity losses for most of the other peaks (except those close to the water resonance, like glucose and carnitine) and not needing gradients to have adequate water suppression, so gradient imperfections do not affect the final spectra, as seen in Figure 1. However, the 1D NOESY presat does have some shortcomings, the main one being the noncomplete suppression of “faraway water”, (20) i.e., water outside of the homogeneous part of the NMR volume, which does not experience the same frequency as the rest of the water.

Figure 1

Figure 1. Zoom of the 1D NOESY presat spectra overlay of pooled urine without (black) and with (red) gradients, along with the complete spectrum shown above, to show the difference in residual water peak intensity.

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Alternate Water Suppression Techniques and Avoiding Some of Their Shortcomings

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Some of the water suppression techniques cited above are more efficient at suppressing faraway water, along with pulse sequence variants aimed at suppressing faraway water, like PRESAT180 (21) or WET180. (22) However, they either use shaped pulses or gradients, which limits the robustness and thus reproducibility of the pulse sequence, an important requirement for metabolomics applications. Among these alternatives, PURGE (19) was developed for applications requiring extensive solvent suppression (LC–NMR, metabolomics, protein study, etc.).
Since its first publication, the PURGE pulse sequence has been used on a regular basis by the team that created it, (23-35) along with several other groups, (36-46) and even suggested in a Nature protocol. (47) Despite this visibility, the PURGE pulse sequence has not become routine in metabolomics. The relative lack of popularity may come from a lack of familiarity by a majority of NMR-based metabolomics researchers and/or an important shortcoming of the PURGE pulse sequence, namely, sensitivity to gradient imperfections.
This sensitivity to gradient imperfections is apparent in our relatively new 600 MHz AVIII-HD, as shown on a sample of glucose in water (Figure 2b). This spectrometer is equipped with a cryoprobe and is currently the main spectrometer for our high-throughput metabolomics studies, which means the PURGE pulse sequence is not the best fit for most of our metabolomics studies due to its poor line shape performance. This issue has also been mentioned in at least one other paper. (44) However, a recent study (48) showed that pulse sequences sensitive to gradient imperfections could still give good line shape by alternating gradient signs between scans. In that case, the WATERGATE water suppression scheme was used, but as we show here the scheme seems to be useful for other pulse sequences, including PURGE.

Figure 2

Figure 2. Pulse sequences for the original PURGE and the optimized PURGE (a), where gradient signs are inverted between every scan. The gradient levels themselves are shown for the original PURGE. d20 and d21 are the delays used within the pulse sequence for short presaturation times and were set to 200 μs, the recommend values. 1D 1H spectra of glucose with the original PURGE (b) and the optimized PURGE (c) pulse sequences, with the water peak framed in red, showing the nonexistent impact of alternating gradients on the water peak. 1D 1H spectra of a urine sample with the original PURGE (d) and the optimized PURGE (e) pulse sequences. An expansion of part e is shown in part f, where both the 1D NOESY presat (red) and the PURGE (black) spectra of 10 urine samples are superimposed. A more global view of the water peak is shown in the framed inset (g).

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We modified the standard PURGE to an “optimized” PURGE sequence by applying gradients that alternated in sign between scans (Figure 2a), similar to the ROBUST-5 approach of Aguilar and co-workers. (48) While we started by including both alternating gradients and prefocusing gradients, we found an increase in the water resonance using prefocusing gradients (data not shown). Therefore, we kept only the alternating gradients. On a concentrated glucose sample (100 mM), the original PURGE shows sensitivity to gradient imperfections, which causes line shape distortions (Figure 2b), while the optimized PURGE shows good line shape and baseline without modification of the water peak (Figure 2c).
After verifying the optimized PURGE on the glucose sample, we compared it to 1D NOESY preset using 10 replicates of pooled human urine samples containing a high concentration of salts and 90% H2O. In these conditions, the optimized PURGE still showed good line shape and baseline compared to the original PURGE (Figure 2d,e). Spectra from each pulse sequence are shown in Figure 2f. This figure shows that the water peak in 1D NOESY presat distorted the baseline over a bigger chemical shift range than for PURGE. This property is probably caused by an incomplete suppression of “faraway water”, as seen in the framed expansion in Figure 2g. In addition, the resonances closest to the water have a higher intensity in the PURGE spectrum, despite using the same presaturation power for both experiments. Our results confirm the utility of the PURGE pulse sequence, especially with the rather simple solution to compensate for gradient imperfections. (48) It should be noted that it is possible to adjust the pre-emphasis on most gradients. However, this is time-consuming and also specific for each probe. Alternating the sign of the gradients provides a much simpler and robust solution to the problem.

T2 Filter

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For samples with a large quantity of macromolecules (like proteins or lipids), T2 filters are useful in order to remove the broad unwanted resonances, as seen in Figure 3b. The pulse sequence mainly used for T2 filters is the CPMG, (10) which has been used for decades. However, a variant called PROJECT has been developed recently, which has some distinct advantages with no significant downsides (Figure 3a). (49) This variant uses perfect echoes instead of spin echoes, an approach developed in 1989 (50) but recently reintroduced after it was shown that it can avoid J-modulation for most spin systems, in contrast to CPMG. (49)

Figure 3

Figure 3. 1D 1H spectrum of whole plasma with 1D NOESY presat and CPMG presat, using standardized parameters (3) (a), along with a close-up of the CPMG presat spectrum, showing in green frame regions where there is still some significant signal from macromolecules (b). The use of a longer T2 filter allows reducing further signals from macromolecules (c), but the use of longer spin echoes (without changing the length of the T2 filter) decreases the sensitivity of signals and even distorts the line shape of some of them (d). The use of the PROJECT pulse sequence as shown in (e) and compared to the CPMG pulse sequence, allows retaining sensitivity when using longer spin echoes (f).

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Since the first publication of PROJECT, a few other papers have shown its utility for T2 measurements or as a T2 filter. (51-57) However, a large number of the references to PROJECT use it as an alternative spin echo for other pulse sequences, (58-65) like WATERGATE, HSQC, INEPT, etc. To our knowledge there has been no mention of PROJECT for metabolomics. For that reason, we were interested to compare PROJECT with CPMG, especially for the quantification of plasma or serum, along with intact tissues with HR-MAS, as shown elsewhere. (54) It should be noted that no new parameters had to be introduced in the PROJECT pulse sequence, so it should be as robust and simple as CPMG.
We compared intact plasma with methanol/water extracted plasma (66, 67) using the same pooled Red Cross plasma that is used for quality control in the Southeast Center for Integrated Metabolomics (SECIM). Intact plasma allows for the comparison between CPMG presat and PROJECT presat, while extracted plasma was used as the standard in terms of quantification. (67) It should be noted that, as described by Gowda and co-workers, extracted plasma or serum produce excellent results. However, it adds extra steps to the sample preparation and also removes the lipoproteins, which can be analyzed directly on the same sample to obtain additional information. (68-70) We first applied CPMG presat with standardized parameters for metabolomics with plasma (Figure 3b). (3) While most of the macromolecular signals are already suppressed, a close examination of the baseline shows that some broad signal remains (Figure 3c). These residual signals can interfere with quantification, so we first tried to increase the length of the T2 filter.
In order to increase the length of T2 and avoid heating the sample, it is preferable to increase the length of each echo rather than the number of echoes. This strategy allows a further reduction of intensity of macromolecules compared to the standardized CPMG presat (Figure 3d). However, when compared to a T2 filter with the same total duration with shorter spin echoes, the CPMG presat with longer spin echoes leads to sensitivity losses for most of the peaks (from 10% to more than 50% in our data set), along with line shape distortion for some peaks that is caused by J-modulation that is not completely suppressed by CPMG presat (Figure 3e). These shortcomings of CPMG presat can be resolved by using the PROJECT presat pulse sequence, which produces spectra almost identical to the one obtained with the CPMG presat using short spin echoes (Figure 3f).
Along with this qualitative overview of the differences in the spectra, we also wanted to determine the effect of the changes in parameters for quantification, results shown in Figure 4. Peaks from 5 different molecules were selected for quantification. These had different properties: isolated peaks (lactate H10 formate H4), peaks with some overlap with macromolecule signals (valine H9-11 and H12-14, α-glucose H19) and peaks with major overlap with macromolecules (lactate H7-9, phenylalanine H13, H14-15, and H16-17). All atom labeling comes from the recently developed ALATIS, which creates a unique and atom-specific InChI string. (71)

Figure 4

Figure 4. CPMG presat spectrum of methanol/water extracted plasma. Assigned peaks used for quantification are displayed. Ten replicate pooled aliquots were prepared for intact and extracted samples (20 total), and each reported pulse sequence was applied to each sample. The bar plots are the mean concentration (in μM) and standard deviation of 10 replicates of each condition, each measured from standard addition, using 3 spectra: one of the extract alone and two after 2 consecutive standard additions of each quantified metabolite. For this figure, the different variants correspond to different parameters (designated in the legend) and not different pulse sequences. CPMG-A, CPMG-B, CPMG-C, and PROJECT-A were used on intact plasma, while NOESYPR1d, PURGE, PROJECT-B, and CPMG-D were used on extracted plasma. τ, spin echo delay between two pulses; τmax, total duration of the spin echo. The parameters for CPMG-A are considered standard for analysis of intact plasma. For each peak, t tests were done, comparing the results of the CPMG presat of extracted plasma (CPMG-D) to the 7 other spectra. *, p < 0.05; **, p < 0.005; ***, p < 0.0005.

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For each selected resonance, quantification was done on both intact and extracted plasma (67) by integrating the area under each resonance and by using standard addition to build the calibration curves. The spiking buffer was identical to that used for the original samples. The single spiking solution contained 55 mM lactate, 57 mM glucose, 10 mM valine, 11 mM phenylalanine, and 0.55 mM formate. We added 20 μL of this solution and recorded all 1D experiments for each spike; this was done twice. For extracted plasma, all pulse sequences mentioned in this paper (noesypr1d, PURGE, cpmgpr1d, and PROJECTpr1d) were tested, using the standard parameters. (3, 67)
t tests for each selected resonance were performed to statistically evaluate the changes in quantification between the different pulse sequences, using a threshold of 0.05 for the p-value. The concentrations from the CPMG presat spectra of the extracted plasma were used as the reference standards. These analyses show two trends. First, the pulse sequences that show the greatest differences with the CPMG presat of extracted plasma are the ones without T2 filters (noesypr1d, PURGE), even though these all used the extracted plasma. This shows that the remaining proteins after extraction are still concentrated enough to interfere with 1D quantification, demonstrating the need for a T2 filter. (67) This difference can be mainly explained by the influence of protein signals in the total area under some of the peaks, especially lactate H7-9, both valine peaks, and α-glucose H19. For phenylalanine, in addition to some interfering protein signal, the different results can be explained by low signal-to-noise (S/N) and the longer T2 filters that further reduce the S/N.
Second, increasing the length of the T2 filter in intact plasma tends toward the values from the CPMG of the extracted plasma. The main exceptions are the phenylalanine peaks, as mentioned above. It can also be noted that for quantification, the length of the T2 filters is more important than the length of the spin echoes or the variant of T2 filter.
Results show that while both CPMG presat and PROJECT presat can be used for quantification, samples with high amount of proteins need long T2 filters, and PROJECT gave better results in these conditions, due to better overall sensitivity and line shape.
In summary, we have shown that there are useful alternatives to the most commonly used 1D NMR metabolomics pulse sequences. Should everyone adopt these in their metabolomics workflow? The answer to this question is complicated by the opposing need for the field to move toward standardization so that data can be compared across studies and between different laboratories. One could argue that it is more important to keep protocols like pulse sequences constant than to further optimize, but this argument is countered by each new generation of instrumentation that is available, which will undoubtedly have a significant impact on the spectra or we would not be willing to pay large amounts of money to buy them. The good news is that the sequences described here produce similar results to their currently used counterparts. In our hands, the optimized PURGE pulse sequence improved the water region when compared with noesypr1d for all samples tested, but other regions of the spectra were essentially unchanged. For plasma or serum, things are more complicated, because every combination of pulse sequence and sample preparation method gives different quantitative values. We think that we understand these differences and have attempted to describe them here. Our recommendation is to use PROJECT presat in place of CPMG presat for intact or extracted samples, because there is no change in parameter optimization and no change for most resonances. However, there is a great improvement when longer T2 filters need to be applied, because PROJECT does not cause J-coupling distortions that arise in CPMG. As the field advances and new techniques are introduced, the best way to establish back-compatibility with older data sets and methods will be to employ a reference standard, such as the NIST plasma (SRM 1950). (72)

Author Information

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  • Corresponding Author
    • Arthur S. Edison - †Complex Carbohydrate Research Center (CCRC), ‡Departments of Genetics and Biochemistry & Molecular Biology, and §Institute of Bioinformatics, University of Georgia, 315 Riverbend Road, Athens, Georgia 30602, United States;  Orcidhttp://orcid.org/0000-0002-5686-2350;  Email: [email protected]
  • Authors
    • Adrien Le Guennec - †Complex Carbohydrate Research Center (CCRC), ‡Departments of Genetics and Biochemistry & Molecular Biology, and §Institute of Bioinformatics, University of Georgia, 315 Riverbend Road, Athens, Georgia 30602, United States
    • Fariba Tayyari - †Complex Carbohydrate Research Center (CCRC), ‡Departments of Genetics and Biochemistry & Molecular Biology, and §Institute of Bioinformatics, University of Georgia, 315 Riverbend Road, Athens, Georgia 30602, United States
  • Author Contributions

    A.L.G conceived the study, implemented the pulse sequences, and measured and analyzed the data. F.T. assisted with extraction protocols and data analysis. All authors contributed to writing the manuscript.

  • Notes
    The authors declare no competing financial interest.

    The raw data used in this study will be deposited in the Metabolomics Workbench.

Acknowledgment

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This work was supported by the Southeast Center for Integrated Metabolomics (Grant NIH/NIDDK U24DK097209) and the Georgia Research Alliance.

References

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    How the 1D-NOESY suppresses solvent signal in metabonomics NMR spectroscopy: an examination of the pulse sequence components and evolution
    McKay, Ryan T.
    Concepts in Magnetic Resonance, Part A: Bridging Education and Research (2011), 38A (5), 197-220CODEN: CMRPC2; ISSN:1546-6086. (Wiley-Blackwell)
    A review. Metabonomics has become an increasingly shared pursuit in international research. Presently the two most common techniques are mass spectrometry and NMR (NMR) spectrometry either in isolation or in conjunction. The 1D-1H-NOESY is the most utilized NMR pulse sequence for the collection of metabonomics NMR data from biol. samples such as blood plasma, serum, urine, cerebrospinal fluid, sputum, or homogenized tissue exts. While the 1D version of the 2D-1H,1H-NOESY pulse sequence has become widely used in metabonomics studies, the understanding of the mechanism of solvent suppression has not kept pace. This article will examine the mechanisms by which the 1D-NOESY suppresses solvent signals and detail the pulse sequence's components in terms of function, phase cycle, and performance.
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    Carr, H. Y.; Purcell, E. M. Phys. Rev. 1954, 94, 630– 638 DOI: 10.1103/PhysRev.94.630
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    Effects of diffusion on free precession in nuclear magnetic resonance experiments
    Carr, H. Y.; Purcell, E. M.
    Physical Review (1954), 94 (), 630-8CODEN: PHRVAO; ISSN:0031-899X.
    Nuclear resonance techniques involving free precession are examd., and a convenient variation of Hahn's spin-echo method is described (ibid. 80, 580(1950)). This variation employs a combination of pulses of different intensity or duration ("90°" and "180°" pulses). Measurements of the transverse relaxation time T2 in fluids are often severely compromised by mol. diffusion. Hahn's analysis of the effect of diffusion is reformulated and extended, and a new scheme for measuring T2 is described which, as predicted by the extended theory, largely circumvents the diffusion effect. On the other hand, the free precession technique, applied in a different way, permits a direct measurement of the mol. self-diffusion const. in suitable fluids. A measurement of the self-diffusion const. of H2O at 25° yields D = 2.5 ± 0.3 × 10-5 sq. cm./sec., in good agreement with previous detns. The effect of convection on free precession is also analyzed. A null method for measuring the longitudinal relaxation time T1, based on the unequal-pulse technique, is described.
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    Meiboom, S.; Gill, D. Rev. Sci. Instrum. 1958, 29, 688– 691 DOI: 10.1063/1.1716296
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    Modified spin-echo method for measuring nuclear relaxation times
    Meiboom, S.; Gill, D.
    Review of Scientific Instruments (1958), 29 (), 688-91CODEN: RSINAK; ISSN:0034-6748.
    The Carr-Purcell method for the measurement of long nuclear relaxation times in liquids (cf. CA 48, 8077e) has been further modified. While the pulse sequence of the modified technique was identical to the original scheme, the necessity of a very accurate adjustment of the 180° pulses was eliminated and the reproducibility was improved. A schematic diagram of the transmitter gate used in the app. is discussed, and the derivation and principle of the method is explained.
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    Hoult, D. I. J. Magn. Reson. (1969-1992) 1976, 21, 337– 347 DOI: 10.1016/0022-2364(76)90081-0
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    Solvent peak saturation with single phase and quadrature Fourier transformation
    Hoult, D. I.
    Journal of Magnetic Resonance (1969-1992) (1976), 21 (2), 337-47CODEN: JOMRA4; ISSN:0022-2364.
    Working on the assumption that satn. of a solvent peak is, in most cases, the best method of reducing the dynamic range of a free induction decay from a soln. of low concn., the factors involved in obtaining a redn. of the order of a thousandfold are discussed. The differing requirements for single phase and quadrature Fourier transform expts. are demonstrated, and the effects of inhomogeneities in B0 and B1 highlighted. Modulation of B0, caused, for example, by spinning the sample, can have a profound effect upon the transient nutation of the magnetization, causing spin-locking in a 2nd rotating frame.
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    Bax, A. J. Magn. Reson. (1969-1992) 1985, 65, 142– 145 DOI: 10.1016/0022-2364(85)90383-X
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    Ogg, R. J.; Kingsley, R. B.; Taylor, J. S. J. Magn. Reson., Ser. B 1994, 104, 1– 10 DOI: 10.1006/jmrb.1994.1048
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    WET, a T1- and B1-insensitive water-suppression method for in vivo localized 1H NMR spectroscopy
    Ogg, Robert J.; Kingsley, Peter B.; Taylor, June S.
    Journal of Magnetic Resonance, Series B (1994), 104 (1), 1-10CODEN: JMRBE5; ISSN:1064-1866.
    Suppression of the water signal during 1H magnetic resonance spectroscopy by repeated sequences of a frequency-selective radiofrequency pulse and a gradient dephasing pulse requires nulling of the longitudinal component of the water magnetization and is therefore affected by T1 relaxation, RF-pulse flip angles (which depend on B1), and sequence timing. In in vivo applications, T1 and B1 inhomogeneity within the sample may cause spatially inhomogeneous water suppression. An improved water-suppression technique called WET (water suppression enhanced through T1 effects), developed from a Bloch equation anal. of the longitudinal magnetization over the T1 and B1 ranges of interest, achieves T1- and B1-insensitive suppression with four RF pulses, each having a numerically optimized flip angle. Once flip angles have been optimized for a given sequence, time-consuming flip-angle adjustments during clin. examns. are eliminated. This water-suppression technique was characterized with respect to T1 variations, B1 variations, off-resonance effects, and partial satn. effects and was compared to similar techniques. Effective water suppression has been achieved with this new technique in single-voxel spectroscopy examns. of >50 brain tumor patients at 1.5 T.
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    Smallcombe, S. H.; Patt, S. L.; Keifer, P. A. J. Magn. Reson., Ser. A 1995, 117, 295– 303 DOI: 10.1006/jmra.1995.0759
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    WET solvent suppression and its applications to LC NMR and high-resolution NMR spectroscopy
    Smallcombe, Stephen H.; Patt, Steven L.; Keifer, Paul A.
    Journal of Magnetic Resonance, Series A (1995), 117 (2), 295-303CODEN: JMRAE2; ISSN:1064-1858. (Academic)
    A review, with 29 refs., is given on recent developments on solvent suppression problems and their applications to liq. chromatog. with NMR detection.
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    Hwang, T. L.; Shaka, A. J. J. Magn. Reson., Ser. A 1995, 112, 275– 279 DOI: 10.1006/jmra.1995.1047
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    Water suppression that works. Excitation sculpting using arbitrary waveforms and pulsed field gradients
    Hwang, Tsang-Lin; Shaka, A. J.
    Journal of Magnetic Resonance, Series A (1995), 112 (2), 275-9CODEN: JMRAE2; ISSN:1064-1858. (Academic)
    A water suppression technique which can applied to most NMR expts. is described. A simple echo sequence employing a pulsed field gradient before and after the refocusing element is applied. Theor. background and examples are gives.
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    Liu, M.; Mao, X.-a.; Ye, C.; Huang, H.; Nicholson, J. K.; Lindon, J. C. J. Magn. Reson. 1998, 132, 125– 129 DOI: 10.1006/jmre.1998.1405
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    Improved WATERGATE pulse sequences for solvent suppression in NMR spectroscopy
    Liu, Maili; Mao, Xi-An; Ye, Chaohui; Huang, He; Nicholson, Jeremy K.; Lindon, John C.
    Journal of Magnetic Resonance (1998), 132 (1), 125-129CODEN: JMARF3; ISSN:1090-7807. (Academic Press)
    Modifications to the WATERGATE method for removing the solvent resonance from 1H NMR spectra are presented. In the conventional WATERGATE, a pulse train with three pairs of sym. pulses in the form 3α-τ-9α-τ-19α-τ-19α-τ-9α-τ-3α (designated here W3), where 26α = 180°, was used, while the improved versions use four and five pairs of sym. pulses (designated here W4 and W5), resp. The modified methods provide narrower noninversion regions and hence enhance the sensitivities of the peaks close to the H2O resonance. The inversion and suppression profiles of the pulse trains W3, W4, and W5 are compared theor. and exptl. and good agreement was obtained.
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    Piotto, M.; Saudek, V.; Sklenář, V. J. Biomol. NMR 1992, 2, 661– 665 DOI: 10.1007/BF02192855
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    Gradient-tailored excitation for single-quantum NMR spectroscopy of aqueous solutions
    Piotto, Martial; Saudek, Valdimir; Sklenar, Vladimir
    Journal of Biomolecular NMR (1992), 2 (6), 661-5CODEN: JBNME9; ISSN:0925-2738.
    A novel approach to tailored selective excitation for the measurement of NMR spectra in non-deuterated aq. solns. (WATERGATE, WATER suppression by GrAdient-Tailored Excitation) is described. The gradient echo sequence, which effectively combines one selective 180° radiofrequency pulse and two field gradient pulses, achieves highly selective and effective water suppression. This technique is ideally suited for the rapid collection of multi-dimensional data since a single-scan acquisition produces a pure phase NMR spectrum with a perfectly flat baseline, at the highest possible sensitivity. Application to the fast measurement of 2D NOE data of a 2.2. mM soln. of a double-stranded DNA fragment in 90% H2O at 5° is presented.
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    Sklenar, V.; Piotto, M.; Leppik, R.; Saudek, V. J. Magn. Reson., Ser. A 1993, 102, 241– 245 DOI: 10.1006/jmra.1993.1098
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    Gradient-tailored water suppression for proton-nitrogen-15 HSQC experiments optimized to retain full sensitivity
    Sklenar, Vladimir; Piotto, Martial; Leppik, Raymond; Saudek, Vladimir
    Journal of Magnetic Resonance, Series A (1993), 102 (2), 241-5CODEN: JMRAE2; ISSN:1064-1858.
    The authors demonstrate that a new tailored excitation scheme for efficient water suppression can be incorporated into phase-sensitive multidimensional NMR expts. with a heteronuclear single-quantum coherence (HSQC) step. This approach allows the carrier to be placed in the center of a protein amide region to maximize the digital resoln. in the acquisition domain. The gradient pulses are applied to suppress the water signal and signals of protons not coupled to 15N nuclei. The pulse schemes for the phase-sensitive 2D HSQC and 3D NOESY-HSQC expts. are diagrammed. Illustrative results are presented for a 1 mM sample of a uniformly 15N-labeled fragment of the transcriptional activator Jun in 90% H2O/10% D2O.
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    Simpson, A. J.; Brown, S. A. J. Magn. Reson. 2005, 175, 340– 346 DOI: 10.1016/j.jmr.2005.05.008
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    Giraudeau, P.; Silvestre, V.; Akoka, S. Metabolomics 2015, 11, 1041– 1055 DOI: 10.1007/s11306-015-0794-7
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    Mo, H.; Raftery, D. J. Magn. Reson. 2008, 190, 1– 6 DOI: 10.1016/j.jmr.2007.09.016
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    Pre-SAT180, a simple and effective method for residual water suppression
    Mo, Huaping; Raftery, Daniel
    Journal of Magnetic Resonance (2008), 190 (1), 1-6CODEN: JMARF3; ISSN:1090-7807. (Elsevier)
    Water located outside the NMR detection coil experiences a reduced RF field intensity. This "faraway water" is known to be very difficult to suppress and often gives rise to a large residual solvent signal. Pre-SAT180 (Pre-Satn. with Adiabatic Toggling of 180 degree pulse inversion) is proposed to cancel the residual water contribution efficiently. Compared with several popular methods such as 1D NOESY with pre-satn. or 270° excitation, Pre-SAT180 has a no. of advantages, including: full retention of signal intensity and selectivity, good phase properties, easy setup, and high tolerance to pulse missettings.
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  22. 22
    Mo, H.; Raftery, D. J. Biomol. NMR 2008, 41, 105– 111 DOI: 10.1007/s10858-008-9246-2
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  23. 23
    McKelvie, J. R.; Yuk, J.; Xu, Y.; Simpson, A. J.; Simpson, M. J. Metabolomics 2009, 5, 84 DOI: 10.1007/s11306-008-0122-6
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  24. 24
    Brown, S. A. E.; Simpson, A. J.; Simpson, M. J. Environmental Chemistry 2009, 6, 432– 440 DOI: 10.1071/EN09054
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    24
    1H NMR metabolomics of earthworm responses to sub-lethal PAH exposure
    Brown, Sarah A. E.; Simpson, Andre J.; Simpson, Myrna J.
    Environmental Chemistry (2009), 6 (5), 432-440CODEN: ECNHAA; ISSN:1449-8979. (CSIRO Publishing)
    Metabolic responses of earthworm exposure to the polycyclic arom. hydrocarbons (PAHs) naphthalene, phenanthrene and pyrene in contact tests were measured using 1H NMR. Novel metabolites were not detected but principal component anal. (PCA) showed that earthworms exposed to 10, 50, and 100 μg cm-2 naphthalene, phenanthrene and pyrene differed from unexposed (control) earthworms. Partial least-squares-discriminant anal. (PLS-DA) showed that earthworms had statistically significant responses to PAH exposure, except for 10 μg/cm-2 naphthalene and 50 μg/cm-2 pyrene. Leucine, valine, alanine, lysine, and maltose were identified as potential response indicators of PAH exposure, but whether the concn. of these metabolites increased or decreased was PAH- and concn.-dependent. These initial findings reveal the potential of metabolomics for monitoring earthworm responses to sub-lethal PAH exposure and highlight the role of metabolomics as a future tool in ecotoxicol.
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  25. 25
    Brown, S. A. E.; McKelvie, J. R.; Simpson, A. J.; Simpson, M. J. Environ. Pollut. 2010, 158, 2117– 2123 DOI: 10.1016/j.envpol.2010.02.023
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  26. 26
    Whitfield Åslund, M. L.; Simpson, A. J.; Simpson, M. J. Ecotoxicology 2011, 20, 836– 846 DOI: 10.1007/s10646-011-0638-9
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  27. 27
    Woods, G. C.; Simpson, M. J.; Koerner, P. J.; Napoli, A.; Simpson, A. J. Environ. Sci. Technol. 2011, 45, 3880– 3886 DOI: 10.1021/es103425s
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  28. 28
    Whitfield Åslund, M.; Simpson, M. J.; Simpson, A. J.; Zeeb, B. A.; Rutter, A. Ecotoxicology 2012, 21, 1947– 1956 DOI: 10.1007/s10646-012-0928-x
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  29. 29
    Lankadurai, B.; Furdui, V.; Reiner, E.; Simpson, A.; Simpson, M. Metabolites 2013, 3, 718 DOI: 10.3390/metabo3030718
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  30. 30
    Lankadurai, B. P.; Wolfe, D. M.; Whitfield Åslund, M. L.; Simpson, A. J.; Simpson, M. J. Metabolomics 2013, 9, 44– 56 DOI: 10.1007/s11306-012-0427-3
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  31. 31
    Lankadurai, B. P.; Nagato, E. G.; Simpson, A. J.; Simpson, M. J. Ecotoxicol. Environ. Saf. 2015, 120, 48– 58 DOI: 10.1016/j.ecoenv.2015.05.020
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  32. 32
    Marshall, M. H. M.; McKelvie, J. R.; Simpson, A. J.; Simpson, M. J. Appl. Geochem. 2015, 54, 43– 53 DOI: 10.1016/j.apgeochem.2014.12.013
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    32
    Characterization of natural organic matter in bentonite clays for potential use in deep geological repositories for used nuclear fuel
    Marshall, Michaela H. M.; McKelvie, Jennifer R.; Simpson, Andre J.; Simpson, Myrna J.
    Applied Geochemistry (2015), 54 (), 43-53CODEN: APPGEY; ISSN:0883-2927. (Elsevier Ltd.)
    The Nuclear Waste Management Organization (NWMO) is developing a Deep Geol. Repository (DGR) to contain and isolate used nuclear fuel in a suitable rock formation at a depth of approx. 500 m. The design concept employs a multibarrier system, including the use of copper-coated used fuel containers, surrounded by a low-permeability, swelling clay buffer material within a low permeability, stable host rock environment. The natural org. matter (NOM) compn. of the bentonite clays being considered for the buffer material is largely uncharacterized at the mol.-level. To gain a better understanding of the NOM in target clays from Wyoming and Saskatchewan, mol.-level methods (biomarker anal., solid-state 13C NMR and soln.-state 1H NMR (NMR)) were used to elucidate the structure and sources of NOM. Org. carbon content in three com. available bentonites analyzed was low (0.11-0.41%). The aliph. lipid distribution of the clay samples analyzed showed a predominance of higher concn. of lipids from vascular plants and low concns. of lipids consistent with microbial origin. The lignin phenol vanillyl acid to aldehyde ratio (Ad/Al) for the National sample indicated an advanced state of lignin oxidn. and NOM diagenesis. The 13C NMR spectra were dominated by signals in the arom. and aliph. regions. The ratio of alkyl/O-alkyl carbon ranged from 7.6 to 9.7, indicating that the NOM has undergone advanced diagenetic alteration. The absence lignin-derived phenols commonly obsd. in CuO oxidn. exts. from contemporary soils and sediments as well as the lack of amino acids suggests that the material corresponding to the arom. signal is not composed of lignin or proteins but may be derived from another source such as black carbon or some other non-extractable arom.-rich NOM. The aliph. signal appears to correspond to long-chain compds. with little side branching based on the results of the one-dimensional (1D) and two-dimensional (2D) soln.-state 1H NMR analyses. Overall, the org. geochem. analyses suggest that the NOM is composed mainly of plant-derived waxes and highly arom. carbon with low contributions from small mols. The compds. identified by the mol.-level anal. of NOM in the clay samples are hypothesized to be recalcitrant but future studies should examine if these compds. may serve as a microbial substrate to further test the observations of this study. Furthermore, our study suggests that the NOM has undergone diagenesis and that marine NOM signatures are no longer recognizable or detectable. As such, future work may also examine the diagenesis of these deposits to further understand the NOM geochem. and paleoenvironmental conditions in bentonite deposits.
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  33. 33
    Kovacevic, V.; Simpson, A. J.; Simpson, M. J. Comp. Biochem. Physiol., Part D: Genomics Proteomics 2016, 19, 199– 210 DOI: 10.1016/j.cbd.2016.01.004
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    33
    1H NMR-based metabolomics of Daphnia magna responses after sub-lethal exposure to triclosan, carbamazepine and ibuprofen
    Kovacevic, Vera; Simpson, Andre J.; Simpson, Myrna J.
    Comparative Biochemistry and Physiology, Part D: Genomics & Proteomics (2016), 19 (), 199-210CODEN: CBPPBG; ISSN:1744-117X. (Elsevier B.V.)
    Pharmaceuticals and personal care products are a class of emerging contaminants that are present in wastewater effluents, surface water, and groundwater around the world. There is a need to det. rapid and reliable bioindicators of exposure and the toxic mode of action of these contaminants to aquatic organisms. 1H NMR (NMR)-based metabolomics in combination with multivariate statistical anal. was used to det. the metabolic profile of Daphnia magna after exposure to a range of sub-lethal concns. of triclosan (6.25-100 μg/L), carbamazepine (1.75-14 mg/L) and ibuprofen (1.75-14 mg/L) for 48 h. Sub-lethal triclosan exposure suggested a general oxidative stress condition and the branched-chain amino acids, glutamine, glutamate, and methionine emerged as potential bioindicators. The arom. amino acids, serine, glycine and alanine are potential bioindicators for sub-lethal carbamazepine exposure that may have altered energy metab. The potential bioindicators for sub-lethal ibuprofen exposure are serine, methionine, lysine, arginine and leucine, which showed a concn.-dependent response. The differences in the metabolic changes were related to the dissimilar modes of toxicity of triclosan, carbamazepine and ibuprofen. 1H NMR-based metabolomics gave an improved understanding of how these emerging contaminants impact the keystone species D. magna.
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  34. 34
    Nagato, E. G.; Simpson, A. J.; Simpson, M. J. Aquat. Toxicol. 2016, 170, 175– 186 DOI: 10.1016/j.aquatox.2015.11.023
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    34
    Metabolomics reveals energetic impairments in Daphnia magna exposed to diazinon, malathion and bisphenol-A
    Nagato, Edward G.; Simpson, Andre J.; Simpson, Myrna J.
    Aquatic Toxicology (2016), 170 (), 175-186CODEN: AQTODG; ISSN:0166-445X. (Elsevier B.V.)
    1H NMR (NMR)-based metabolomics was used to study the response of Daphnia magna to increasing sub-lethal concns. of either an organophosphate (diazinon or malathion) or bisphenol-A (BPA). Principal component anal. (PCA) of 1H NMR spectra were used to screen metabolome changes after 48 h of contaminant exposure. The PCA scores plots showed that diazinon exposures resulted in aberrant metabolomic profiles at all exposure concns. tested (0.009-0.135 μg/L), while for malathion the second lowest (0.08 μg/L) and two highest exposure concns. (0.32 μg/L and 0.47 μg/L) caused significant shifts from the control. Individual metabolite changes for both organophosphates indicated that the response to increasing exposure was non-linear and described perturbations in the metabolome that were characteristic of the severity of exposure. For example, intermediate concns. of diazinon (0.045 μg/L and 0.09 μg/L) and malathion (0.08 μg/L) elicited a decrease in amino acids such as leucine, valine, arginine, glycine, lysine, glutamate, glutamine, phenylalanine and tyrosine, with concurrent increases in glucose and lactate, suggesting a mobilization of energy resources to combat stress. At the highest exposure concns. for both organophosphates there was evidence of a cessation in metabolic activity, where the same amino acids increased and glucose and lactate decreased, suggesting a slowdown in protein synthesis and depletion of energy stocks. This demonstrated a similar response in the metabolome between two organophosphates but also that intermediate and severe stress levels could be differentiated by changes in the metabolome. For BPA exposures, the PCA scores plot showed a significant change in metabolome at 0.1 mg/L, 1.4 mg/L and 2.1 mg/L of exposure. Individual metabolite changes from 0.7 to 2.1 mg/L of BPA exposure showed increases in amino acids such as alanine, valine, isoleucine, leucine, arginine, phenylalanine and tyrosine. These metabolite changes were correlated with decreases in glucose and lactate. This pattern of response was also seen in the highest organophosphate exposures and suggested a generalized stress response that could be related to altered energy dynamics in D. magna. Through studying increasing exposure responses, we have demonstrated the ability of metabolomics to identify discrete differences between intermediate and severe stress, and also to characterize how systemic stress is manifested in the metabolome.
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  35. 35
    Wagner, N. D.; Simpson, A. J.; Simpson, M. J. Environ. Toxicol. Chem. 2017, 36, 938– 946 DOI: 10.1002/etc.3604
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  36. 36
    Hölscher, D.; Brand, S.; Wenzler, M.; Schneider, B. J. Nat. Prod. 2008, 71, 251– 257 DOI: 10.1021/np0705514
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  37. 37
    Byrne, C. M. P.; Hayes, M. H. B.; Kumar, R.; Novotny, E. H.; Lanigan, G.; Richards, K. G.; Fay, D.; Simpson, A. J. Water Res. 2010, 44, 4379– 4390 DOI: 10.1016/j.watres.2010.05.055
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  38. 38
    Lesar, C. T.; Decatur, J.; Lukasiewicz, E.; Champeil, E. Forensic Sci. Int. 2011, 212, e40– e45 DOI: 10.1016/j.forsciint.2011.06.017
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    38
    Report on the analysis of common beverages spiked with gamma-hydroxybutyric acid (GHB) and gamma-butyrolactone (GBL) using NMR and the PURGE solvent-suppression technique
    Lesar, Casey T.; Decatur, John; Lukasiewicz, Elaan; Champeil, Elise
    Forensic Science International (2011), 212 (1-3), e40-e45CODEN: FSINDR; ISSN:0379-0738. (Elsevier Ltd.)
    In forensic evidence, the identification and quantitation of gamma-hydroxybutyric acid (GHB) in "spiked" beverages is challenging. In this report, we present the anal. of common alc. beverages found in clubs and bars spiked with gamma-hydroxybutyric acid (GHB) and gamma-butyrolactone (GBL). Our anal. of the spiked beverages consisted of using 1H NMR with a water suppression method called Presatn. Utilizing Relaxation Gradients and Echoes (PURGE). The following beverages were analyzed: water, 10% ethanol in water, vodka-cranberry juice, rum and coke, gin and tonic, whisky and diet coke, white wine, red wine, and beer. The PURGE method allowed for the direct identification and quantitation of both compds. in all beverages except red and white wine where small interferences prevented accurate quantitation. The NMR method presented in this paper utilizes PURGE water suppression. Thanks to the use of a capillary internal std., the method is fast, non-destructive, sensitive and requires no sample prepn. which could disrupt the equil. between GHB and GBL.
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    Houghton, J. L.; Biswas, T.; Chen, W.; Tsodikov, O. V.; Garneau-Tsodikova, S. ChemBioChem 2013, 14, 2127– 2135 DOI: 10.1002/cbic.201300359
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    Houghton, J. L.; Green, K. D.; Pricer, R. E.; Mayhoub, A. S.; Garneau-Tsodikova, S. J. Antimicrob. Chemother. 2013, 68, 800– 805 DOI: 10.1093/jac/dks497
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    Unexpected N-acetylation of capreomycin by mycobacterial Eis enzymes
    Houghton, Jacob L.; Green, Keith D.; Pricer, Rachel E.; Mayhoub, Abdelrahman S.; Garneau-Tsodikova, Sylvie
    Journal of Antimicrobial Chemotherapy (2013), 68 (4), 800-805CODEN: JACHDX; ISSN:0305-7453. (Oxford University Press)
    The enhanced intracellular survival (Eis) protein from Mycobacterium tuberculosis (EisMtb), a regio-versatile N-acetyltransferase active towards many aminoglycosides (AGs), confers resistance to kanamycin A in some cases of extensively drug-resistant tuberculosis (XDR-TB). We assessed the activity of EisMtb and of its homolog from Mycobacterium smegmatis (EisMsm) against a panel of anti-tuberculosis (TB) drugs and lysine-contg. compds. Both enzymes acetylated capreomycin and some lysine-contg. compds., but not other non-AG non-lysine-contg. drugs tested. Modeling studies predicted the site of modification on capreomycin to be one of the two primary amines in its β-lysine side chain. Using EisMtb, we established via NMR spectroscopy that acetylation of capreomycin occurs on the ε-amine of the β-lysine side chain. Using Msm, we also demonstrated for the first time to our knowledge that acetylation of capreomycin results in deactivation of the drug. Eis is a unique acetyltransferase capable of inactivating the anti-TB drug capreomycin, AGs and other lysine-contg. compds.
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    Pardo Torre, J. C.; Schmidt, G. W.; Paetz, C.; Reichelt, M.; Schneider, B.; Gershenzon, J.; D’Auria, J. C. Phytochemistry 2013, 91, 177– 186 DOI: 10.1016/j.phytochem.2012.09.009
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    Plaza, C.; Courtier-Murias, D.; Fernández, J. M.; Polo, A.; Simpson, A. J. Soil Biol. Biochem. 2013, 57, 124– 134 DOI: 10.1016/j.soilbio.2012.07.026
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    Physical, chemical, and biochemical mechanisms of soil organic matter stabilization under conservation tillage systems: A central role for microbes and microbial by-products in C sequestration
    Plaza, Cesar; Courtier-Murias, Denis; Fernandez, Jose M.; Polo, Alfredo; Simpson, Andre J.
    Soil Biology & Biochemistry (2013), 57 (), 124-134CODEN: SBIOAH; ISSN:0038-0717. (Elsevier B.V.)
    Conservation tillage practices that entail no or reduced soil disturbance are known to help preserve or accumulate soil org. matter (OM). However, the underlying mechanisms esp. at the mol. level are not well understood. In this study soil samples from 25-yr-old exptl. plots continuously cropped with barley (Hordeum vulgare L.) under no-tillage (NT) and chisel tillage (CT) were subjected to a new phys. fractionation method to isolate dissolved OM, mineral-free particulate OM located outside aggregates (phys. and chem. unprotected), OM occluded within both macroaggregates and microaggregates (weakly and strongly protected by phys. mechanisms, resp.), and OM in intimate assocn. with minerals (protected by chem. mechanisms). The whole soils and OM fractions were analyzed for org. C and N content and by modern NMR techniques. The soil under NT stored 16% more org. C and 5% more N than the soil under CT. Compared to CT, NT increased free org. C content by 7%, intra-macroaggregate org. C content by 20%, intra-microaggregate org. C content by 63%, and mineral-assocd. org. C content by 16% and decreased dissolved org. C content by 11%. The mineral-assocd. OM pool accounted for 65% of the difference in total org. C content between NT and CT, whereas the intra-microaggregate OM only explained 18%, intra-macroaggregate OM 14%, and free OM 11%. The NMR expts. revealed that the free and intra-aggregate OM fractions were dominated by crop-derived materials at different stages of decompn., whereas the mineral-assocd. OM pool was predominately of microbial origin. Overall, our results indicate that microbes and microbial byproducts assocd. with mineral surfaces and likely phys. protected by entrapment within very small microaggregates constitute the most important pool of OM stabilization and C sequestration in soils under NT. Most probably the slower macroaggregate turnover in NT relative to CT boosts not only the formation of microaggregates and thereby the phys. protection of crop-derived particulate OM, but more importantly the interaction between mineral particles and microbial material that results in the formation of very stable organo-mineral complexes.
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    Marshall, D. D.; Sadykov, M. R.; Thomas, V. C.; Bayles, K. W.; Powers, R. J. Proteome Res. 2016, 15, 1205– 1212 DOI: 10.1021/acs.jproteome.5b01089
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    Redox Imbalance Underlies the Fitness Defect Associated with Inactivation of the Pta-AckA Pathway in Staphylococcus aureus
    Marshall, Darrell D.; Sadykov, Marat R.; Thomas, Vinai C.; Bayles, Kenneth W.; Powers, Robert
    Journal of Proteome Research (2016), 15 (4), 1205-1212CODEN: JPROBS; ISSN:1535-3893. (American Chemical Society)
    The phosphotransacetylase-acetate kinase (Pta-AckA) pathway is thought to be a vital ATP generating pathway for Staphylococcus aureus. Disruption of the Pta-AckA pathway during overflow metab. causes significant redn. in growth rate and viability, albeit not due to intracellular ATP depletion. Here, we demonstrate that toxicity assocd. with inactivation of the Pta-AckA pathway resulted from an altered intracellular redox environment. Growth of the pta and ackA mutants under anaerobic conditions partially restored cell viability. NMR metabolomics analyses and 13C6-glucose metab. tracing expts. revealed the activity of multiple pathways that promote redox (NADH/NAD+) turnover to be enhanced in the pta and ackA mutants during anaerobic growth. Restoration of redox homeostasis in the pta mutant by overexpressing L- lactate dehydrogenase partially restored its viability under aerobic conditions. Together, our findings suggest that during overflow metab., the Pta-AckA pathway plays a crit. role in preventing cell viability defects by promoting intracellular redox homeostasis.
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    Vučković, I.; Rapinoja, M.-L.; Vaismaa, M.; Vanninen, P.; Koskela, H. Phytochem. Anal. 2016, 27, 64– 72 DOI: 10.1002/pca.2600
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    Application of comprehensive NMR-based analysis strategy in annotation, isolation and structure elucidation of low molecular weight metabolites of Ricinus communis seeds
    Vuckovic, Ivan; Rapinoja, Marja-Leena; Vaismaa, Matti; Vanninen, Paula; Koskela, Harri
    Phytochemical Analysis (2016), 27 (1), 64-72CODEN: PHANEL; ISSN:0958-0344. (John Wiley & Sons Ltd.)
    Introduction : Powder-like ext. of Ricinus communis seeds contain a toxic protein, ricin, which has a history of military, criminal and terroristic use. As the detection of ricin in this "terrorist powder" is difficult and time-consuming, related low mass metabolites have been suggested to be useful for screening as biomarkers of ricin. Objective : To apply a comprehensive NMR-based anal. strategy for annotation, isolation and structure elucidation of low mol. wt. plant metabolites of Ricinus communis seeds. Methodol. : The seed ext. was prepd. with a well-known acetone extn. approach. The common metabolites were annotated from seed ext. dissolved in acidic soln. using 1H NMR spectroscopy with spectrum library comparison and std. addn., whereas unconfirmed metabolites were identified using multi-step off-line HPLC-DAD-NMR approach. Results : In addn. to the common plant metabolites, two previously unreported compds., 1,3-digalactoinositol and ricinyl-alanine, were identified with support of MS analyses. Conclusion : The applied comprehensive NMR-based anal. strategy provided identification of the prominent low mol. wt. metabolites with high confidence. Copyright © 2015 John Wiley & Sons, Ltd.
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    NMR-based metabolomic analysis of plants
    Kim, Hye Kyong; Choi, Young Hae; Verpoorte, Robert
    Nature Protocols (2010), 5 (3), 536-549CODEN: NPARDW; ISSN:1750-2799. (Nature Publishing Group)
    NMR-based metabolomics has many applications in plant science. Metabolomics can be used in functional genomics and to differentiate plants from different origin, or after different treatments. In this protocol, the following steps of plant metabolomics using NMR spectroscopy are described: sample prepn. (freeze drying followed by extn. by ultrasonication with 1:1 CD3OD:KH2PO4 buffer in D2O), NMR anal. (std. 1H, J-resolved, 1H-1H correlation spectroscopy (COSY) and heteronuclear multiple bond correlation (HMBC)) and chemometric methods. The main advantage of NMR metabolomic anal. is the possibility of identifying metabolites by comparing NMR data with refs. or by structure elucidation using two-dimensional NMR. This protocol is particularly suited for the anal. of secondary metabolites such as phenolic compds. (usually abundant in plants), and for primary metabolites (e.g., sugars and amino acids). This procedure is rapid; it takes no more than 30 min for sample prepn. (multiple parallel) and a further 10 min for NMR spectrum acquisition.
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    Spin echo NMR spectra without J modulation
    Aguilar, Juan A.; Nilsson, Mathias; Bodenhausen, Geoffrey; Morris, Gareth A.
    Chemical Communications (Cambridge, United Kingdom) (2012), 48 (6), 811-813CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
    The spin echo is the single most important building block in modern NMR spectroscopy, but echo modulation by scalar couplings J can severely complicate its use. We show for the first time that a general but unacknowledged soln. to such complications already exists.
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    Study of liquid-phase molecular packing interactions and morphology of fatty acid methyl esters (biodiesel)
    Berman, Paula; Meiri, Nitzan; Colnago, Luiz Alberto; Moraes, Tiago Bueno; Linder, Charles; Levi, Ofer; Parmet, Yisrael; Saunders, Michael; Wiesman, Zeev
    Biotechnology for Biofuels (2015), 8 (), 12/1-12/16CODEN: BBIIFL; ISSN:1754-6834. (BioMed Central Ltd.)
    Background:1H low field NMR (LF-NMR) relaxometry has been suggested as a tool to distinguish between different mol. ensembles in complex systems with differential segmental or whole mol. motion and/or different morphologies. In biodiesel applications the mol. structure vs. liq.-phase packing morphologies of fatty acid Me esters (FAMEs) influences physico-chem. characteristics of the fuel, including flow properties, operability during cold weather, blending, and more. Still, their liq. morphol. structures have scarcely been studied. It was therefore the objective of this work to explore the potential of this technol. for characterizing the mol. organization of FAMEs in the liq. phase. This was accomplished by using a combination of supporting advanced technologies. Results:We show that pure oleic acid (OA) and Me oleate (MO) stds. exhibited both similarities and differences in the 1H LF-NMR relaxation times (T2s) and peak areas, for a range of temps. Based on X-ray measurements, both mols. were found to possess a liq. crystal-like order, although a larger fluidity was found for MO, because as the temp. is increased, MO mols. sep. both longitudinally and transversely from one another. In addn., both mols. exhibited a preferred direction of diffusion based on the apparent hydrodynamic radius. The close mol. packing arrangement and interactions were found to affect the translational and segmental motions of the mols., as a result of dimerization of the head group in OA as opposed to weaker polar interactions in MO. Conclusions:Acomprehensive model for the liq. crystal-like arrangement of FAMEs in the liq. phase is suggested. The differences in translational and segmental motions of the mols. were rationalized by the differences in the 1H LF-NMR T2 distributions of OA and MO, which was further supported by 13C high field (HF)-NMR spectra and 1H HF-NMR relaxation. The proposed assignment allows for material characterization based on parameters that contribute to properties in applications such as biodiesel fuels.
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    "Perfecting" WATERGATE: clean proton NMR spectra from aqueous solution
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    Chemical Communications (Cambridge, United Kingdom) (2013), 49 (4), 358-360CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
    A simple modification of the WATERGATE solvent suppression method greatly improves the quality of 1H NMR spectra obtainable from samples in H2O. The new method allows 1H signals to be measured even when close in chem. shift to the signal of H2O, as e.g. in the NMR spectra of carbohydrates.
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    Genetic associations with lipoprotein subfractions provide information on their biological nature
    Petersen, Ann-Kristin; Stark, Klaus; Musameh, Muntaser D.; Nelson, Christopher P.; Roemisch-Margl, Werner; Kremer, Werner; Raffler, Johannes; Krug, Susanne; Skurk, Thomas; Rist, Manuela J.; Daniel, Hannelore; Hauner, Hans; Adamski, Jerzy; Tomaszewski, Maciej; Doering, Angela; Peters, Annette; Wichmann, H.-Erich; Kaess, Bernhard M.; Kalbitzer, Hans Robert; Huber, Fritz; Pfahlert, Volker; Samani, Nilesh J.; Kronenberg, Florian; Dieplinger, Hans; Illig, Thomas; Hengstenberg, Christian; Suhre, Karsten; Gieger, Christian; Kastenmueller, Gabi
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    Adverse levels of lipoproteins are highly heritable and constitute risk factors for cardiovascular outcomes. Hitherto, genome-wide assocn. studies revealed 95 lipid-assocd. loci. However, due to the small effect sizes of these assocns. large sample nos. (>100,000 samples) were needed. Here we show that analyzing more refined lipid phenotypes, namely lipoprotein subfractions, can increase the no. of significantly assocd. loci compared with bulk high-d. lipoprotein and low-d. lipoprotein anal. in a study with identical sample nos. Moreover, lipoprotein subfractions provide novel insight into the human lipid metab. We measured 15 lipoprotein subfractions (L1-L15) in 1791 samples using 1H-NMR spectroscopy. Using cluster analyses, we quantified inter-relationships among lipoprotein subfractions. Addnl., we analyzed assocns. with subfractions at known lipid loci. We identified five distinct groups of subfractions: one (L1) was only marginally captured by serum lipids and therefore extends our knowledge of lipoprotein biochem. During a lipid-tolerance test, L1 lost its special position. In the assocn. anal., we found that eight loci (LIPC, CETP, PLTP, FADS1-2-3, SORT1, GCKR, APOB, APOA1) were assocd. with the subfractions, whereas only four loci (CETP, SORT1, GCKR, APOA1) were assocd. with serum lipids. For LIPC, we obsd. a 10-fold increase in the variance explained by our regression models. In conclusion, NMR-based fine mapping of lipoprotein subfractions provides novel information on their biol. nature and strengthens the assocns. with genetic loci. Future clin. studies are now needed to investigate their biomedical relevance.
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    Unique identifiers for small molecules enable rigorous labeling of their atoms
    Dashti Hesam; Westler William M; Markley John L; Eghbalnia Hamid R
    Scientific data (2017), 4 (), 170073 ISSN:.
    Rigorous characterization of small organic molecules in terms of their structural and biological properties is vital to biomedical research. The three-dimensional structure of a molecule, its 'photo ID', is inefficient for searching and matching tasks. Instead, identifiers play a key role in accessing compound data. Unique and reproducible molecule and atom identifiers are required to ensure the correct cross-referencing of properties associated with compounds archived in databases. The best approach to this requirement is the International Chemical Identifier (InChI). However, the current implementation of InChI fails to provide a complete standard for atom nomenclature, and incorrect use of the InChI standard has resulted in the proliferation of non-unique identifiers. We propose a methodology and associated software tools, named ALATIS, that overcomes these shortcomings. ALATIS is an adaptation of InChI, which operates fully within the InChI convention to provide unique and reproducible molecule and all atom identifiers. ALATIS includes an InChI extension for unique atom labeling of symmetric molecules. ALATIS forms the basis for improving reproducibility and unifying cross-referencing across databases.
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  • Abstract

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    Figure 1

    Figure 1. Zoom of the 1D NOESY presat spectra overlay of pooled urine without (black) and with (red) gradients, along with the complete spectrum shown above, to show the difference in residual water peak intensity.

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    Figure 2

    Figure 2. Pulse sequences for the original PURGE and the optimized PURGE (a), where gradient signs are inverted between every scan. The gradient levels themselves are shown for the original PURGE. d20 and d21 are the delays used within the pulse sequence for short presaturation times and were set to 200 μs, the recommend values. 1D 1H spectra of glucose with the original PURGE (b) and the optimized PURGE (c) pulse sequences, with the water peak framed in red, showing the nonexistent impact of alternating gradients on the water peak. 1D 1H spectra of a urine sample with the original PURGE (d) and the optimized PURGE (e) pulse sequences. An expansion of part e is shown in part f, where both the 1D NOESY presat (red) and the PURGE (black) spectra of 10 urine samples are superimposed. A more global view of the water peak is shown in the framed inset (g).

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    Figure 3

    Figure 3. 1D 1H spectrum of whole plasma with 1D NOESY presat and CPMG presat, using standardized parameters (3) (a), along with a close-up of the CPMG presat spectrum, showing in green frame regions where there is still some significant signal from macromolecules (b). The use of a longer T2 filter allows reducing further signals from macromolecules (c), but the use of longer spin echoes (without changing the length of the T2 filter) decreases the sensitivity of signals and even distorts the line shape of some of them (d). The use of the PROJECT pulse sequence as shown in (e) and compared to the CPMG pulse sequence, allows retaining sensitivity when using longer spin echoes (f).

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    Figure 4

    Figure 4. CPMG presat spectrum of methanol/water extracted plasma. Assigned peaks used for quantification are displayed. Ten replicate pooled aliquots were prepared for intact and extracted samples (20 total), and each reported pulse sequence was applied to each sample. The bar plots are the mean concentration (in μM) and standard deviation of 10 replicates of each condition, each measured from standard addition, using 3 spectra: one of the extract alone and two after 2 consecutive standard additions of each quantified metabolite. For this figure, the different variants correspond to different parameters (designated in the legend) and not different pulse sequences. CPMG-A, CPMG-B, CPMG-C, and PROJECT-A were used on intact plasma, while NOESYPR1d, PURGE, PROJECT-B, and CPMG-D were used on extracted plasma. τ, spin echo delay between two pulses; τmax, total duration of the spin echo. The parameters for CPMG-A are considered standard for analysis of intact plasma. For each peak, t tests were done, comparing the results of the CPMG presat of extracted plasma (CPMG-D) to the 7 other spectra. *, p < 0.05; **, p < 0.005; ***, p < 0.0005.

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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhvFSqur8%253D&md5=c21349c89b429cf945ef335292288124
    5. 5
      Lewis, I. A.; Schommer, S. C.; Markley, J. L. Magn. Reson. Chem. 2009, 47, S123– S126 DOI: 10.1002/mrc.2526
      5
      rNMR: open source software for identifying and quantifying metabolites in NMR spectra
      Lewis, Ian A.; Schommer, Seth C.; Markley, John L.
      Magnetic Resonance in Chemistry (2009), 47 (S1), S123-S126CODEN: MRCHEG; ISSN:0749-1581. (John Wiley & Sons Ltd.)
      Despite the extensive use of NMR for metabolomics, no publicly available tools have been designed for identifying and quantifying metabolites across multiple spectra. The authors introduce here a new open source software tool, rNMR, which provides a simple graphics-based method for visualizing, identifying, and quantifying metabolites across multiple one- or two-dimensional NMR spectra. RNMR differs from existing software tools for NMR spectroscopy in that analyses are based on regions of interest (ROIs) rather than peak lists. ROIs contain all of the underlying NMR data within user-defined chem. shift ranges. ROIs can be inspected visually, and they support robust quantification of NMR signals. ROI-based analyses support simultaneous views of metabolite signals from up to hundreds of spectra, and ROI boundaries can be adjusted dynamically to ensure that signals corresponding to assigned atoms are analyzed consistently throughout the dataset. The authors describe how rNMR greatly reduces the time required for robust bioanal. anal. of complex NMR data. An rNMR anal. yields a compact and transparent way of archiving the results from a metabolomics study so that it can be examd. and evaluated by others. The rNMR website at http://rnmr.nmrfam.wisc.edu offers downloadable versions of rNMR for Windows, Macintosh, and Linux platforms along with extensive help documentation, instructional videos, and sample data. Copyright © 2009 John Wiley & Sons, Ltd.
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    6. 6
      Zhang, F.; Robinette, S. L.; Bruschweiler-Li, L.; Brüschweiler, R. Magn. Reson. Chem. 2009, 47, S118– S122 DOI: 10.1002/mrc.2486
      6
      Web server suite for complex mixture analysis by covariance NMR
      Zhang, Fengli; Robinette, Steven L.; Bruschweiler-Li, Lei; Brueschweiler, Rafael
      Magnetic Resonance in Chemistry (2009), 47 (S1), S118-S122CODEN: MRCHEG; ISSN:0749-1581. (John Wiley & Sons Ltd.)
      Elucidation of the chem. compn. of biol. samples is a main focus of systems biol. and metabolomics. Their comprehensive study requires reliable, efficient, and automatable methods to identify and quantify the underlying metabolites. Because NMR spectroscopy is a rich source of mol. information, it has a unique potential for this task. Here the authors present a suite of public web servers, termed COLMAR, which facilitates complex mixt. anal. by NMR. The COLMAR web portal presently consists of three servers: COLMAR covariance calcs. the covariance NMR spectrum from an NMR input dataset, such as a TOCSY spectrum; COLMAR DemixC method decomps. the 2D covariance TOCSY spectrum into a reduced set of nonredundant 1D cross sections or traces, which belong to individual mixt. components; and COLMAR query screens the traces against a NMR spectral database to identify individual compds. Examples are presented that illustrate the utility of this web server suite for complex mixt. anal. Copyright © 2009 John Wiley & Sons, Ltd.
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    7. 7
      Nicholson, J. K.; Foxall, P. J. D.; Spraul, M.; Farrant, R. D.; Lindon, J. C. Anal. Chem. 1995, 67, 793– 811 DOI: 10.1021/ac00101a004
      7
      750 MHz 1H and 1H-13C NMR Spectroscopy of Human Blood Plasma
      Nicholson, Jeremy K.; Foxall, Peta J. D.; Spraul, Manfred; Farrant, R. Duncan; Lindon, John C.
      Analytical Chemistry (1995), 67 (5), 793-811CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
      High-resoln. 750 MHz 1H NMR spectra of control human blood plasma have been measured and assigned by the concerted use of a range of spin-echo, two-dimensional J-resolved, and homonuclear and heteronuclear (1H-13C) correlation methods. The increased spectral dispersion and sensitivity at 750 MHz enable the assignment of numerous 1H and 13C resonances from many mol. species that cannot be detected at lower frequencies. This work presents the most comprehensive assignment of the 1H NMR spectra of blood plasma yet achieved and includes the assignment of signals from 43 low Mr metabolites, including many with complex or strongly coupled spin systems. New assignments are also provided from the 1H and 13C NMR signals from several important macromol. species in whole blood plasma, i.e., very-low-d., low-d., and high-d. lipoproteins, albumin, and α1-acid glycoprotein. The temp. dependence of the one-dimensional and spin-echo 750 MHz 1H NMR spectra of plasma was investigated over the range 292-310 K. The 1H NMR signals from the fatty acyl side chains of the lipoproteins increased substantially with temp. (hence also mol. mobility), with a disproportionate increase from lipids in low-d. lipoprotein. Two-dimensional 1H-13C heteronuclear multiple quantum coherence spectroscopy at 292 and 310 K allowed both the direct detection of cholesterol and choline species bound in high-d. lipoprotein and the assignment of their signals and confirmed the assignment of most of the lipoprotein resonances.
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    8. 8
      McKay, R. T. Concepts Magn. Reson., Part A 2011, 38A, 197– 220 DOI: 10.1002/cmr.a.20223
      8
      How the 1D-NOESY suppresses solvent signal in metabonomics NMR spectroscopy: an examination of the pulse sequence components and evolution
      McKay, Ryan T.
      Concepts in Magnetic Resonance, Part A: Bridging Education and Research (2011), 38A (5), 197-220CODEN: CMRPC2; ISSN:1546-6086. (Wiley-Blackwell)
      A review. Metabonomics has become an increasingly shared pursuit in international research. Presently the two most common techniques are mass spectrometry and NMR (NMR) spectrometry either in isolation or in conjunction. The 1D-1H-NOESY is the most utilized NMR pulse sequence for the collection of metabonomics NMR data from biol. samples such as blood plasma, serum, urine, cerebrospinal fluid, sputum, or homogenized tissue exts. While the 1D version of the 2D-1H,1H-NOESY pulse sequence has become widely used in metabonomics studies, the understanding of the mechanism of solvent suppression has not kept pace. This article will examine the mechanisms by which the 1D-NOESY suppresses solvent signals and detail the pulse sequence's components in terms of function, phase cycle, and performance.
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    9. 9
      Carr, H. Y.; Purcell, E. M. Phys. Rev. 1954, 94, 630– 638 DOI: 10.1103/PhysRev.94.630
      9
      Effects of diffusion on free precession in nuclear magnetic resonance experiments
      Carr, H. Y.; Purcell, E. M.
      Physical Review (1954), 94 (), 630-8CODEN: PHRVAO; ISSN:0031-899X.
      Nuclear resonance techniques involving free precession are examd., and a convenient variation of Hahn's spin-echo method is described (ibid. 80, 580(1950)). This variation employs a combination of pulses of different intensity or duration ("90°" and "180°" pulses). Measurements of the transverse relaxation time T2 in fluids are often severely compromised by mol. diffusion. Hahn's analysis of the effect of diffusion is reformulated and extended, and a new scheme for measuring T2 is described which, as predicted by the extended theory, largely circumvents the diffusion effect. On the other hand, the free precession technique, applied in a different way, permits a direct measurement of the mol. self-diffusion const. in suitable fluids. A measurement of the self-diffusion const. of H2O at 25° yields D = 2.5 ± 0.3 × 10-5 sq. cm./sec., in good agreement with previous detns. The effect of convection on free precession is also analyzed. A null method for measuring the longitudinal relaxation time T1, based on the unequal-pulse technique, is described.
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    10. 10
      Meiboom, S.; Gill, D. Rev. Sci. Instrum. 1958, 29, 688– 691 DOI: 10.1063/1.1716296
      10
      Modified spin-echo method for measuring nuclear relaxation times
      Meiboom, S.; Gill, D.
      Review of Scientific Instruments (1958), 29 (), 688-91CODEN: RSINAK; ISSN:0034-6748.
      The Carr-Purcell method for the measurement of long nuclear relaxation times in liquids (cf. CA 48, 8077e) has been further modified. While the pulse sequence of the modified technique was identical to the original scheme, the necessity of a very accurate adjustment of the 180° pulses was eliminated and the reproducibility was improved. A schematic diagram of the transmitter gate used in the app. is discussed, and the derivation and principle of the method is explained.
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    11. 11
      Hoult, D. I. J. Magn. Reson. (1969-1992) 1976, 21, 337– 347 DOI: 10.1016/0022-2364(76)90081-0
      11
      Solvent peak saturation with single phase and quadrature Fourier transformation
      Hoult, D. I.
      Journal of Magnetic Resonance (1969-1992) (1976), 21 (2), 337-47CODEN: JOMRA4; ISSN:0022-2364.
      Working on the assumption that satn. of a solvent peak is, in most cases, the best method of reducing the dynamic range of a free induction decay from a soln. of low concn., the factors involved in obtaining a redn. of the order of a thousandfold are discussed. The differing requirements for single phase and quadrature Fourier transform expts. are demonstrated, and the effects of inhomogeneities in B0 and B1 highlighted. Modulation of B0, caused, for example, by spinning the sample, can have a profound effect upon the transient nutation of the magnetization, causing spin-locking in a 2nd rotating frame.
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    12. 12
      Bax, A. J. Magn. Reson. (1969-1992) 1985, 65, 142– 145 DOI: 10.1016/0022-2364(85)90383-X
      There is no corresponding record for this reference.
    13. 13
      Ogg, R. J.; Kingsley, R. B.; Taylor, J. S. J. Magn. Reson., Ser. B 1994, 104, 1– 10 DOI: 10.1006/jmrb.1994.1048
      13
      WET, a T1- and B1-insensitive water-suppression method for in vivo localized 1H NMR spectroscopy
      Ogg, Robert J.; Kingsley, Peter B.; Taylor, June S.
      Journal of Magnetic Resonance, Series B (1994), 104 (1), 1-10CODEN: JMRBE5; ISSN:1064-1866.
      Suppression of the water signal during 1H magnetic resonance spectroscopy by repeated sequences of a frequency-selective radiofrequency pulse and a gradient dephasing pulse requires nulling of the longitudinal component of the water magnetization and is therefore affected by T1 relaxation, RF-pulse flip angles (which depend on B1), and sequence timing. In in vivo applications, T1 and B1 inhomogeneity within the sample may cause spatially inhomogeneous water suppression. An improved water-suppression technique called WET (water suppression enhanced through T1 effects), developed from a Bloch equation anal. of the longitudinal magnetization over the T1 and B1 ranges of interest, achieves T1- and B1-insensitive suppression with four RF pulses, each having a numerically optimized flip angle. Once flip angles have been optimized for a given sequence, time-consuming flip-angle adjustments during clin. examns. are eliminated. This water-suppression technique was characterized with respect to T1 variations, B1 variations, off-resonance effects, and partial satn. effects and was compared to similar techniques. Effective water suppression has been achieved with this new technique in single-voxel spectroscopy examns. of >50 brain tumor patients at 1.5 T.
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    14. 14
      Smallcombe, S. H.; Patt, S. L.; Keifer, P. A. J. Magn. Reson., Ser. A 1995, 117, 295– 303 DOI: 10.1006/jmra.1995.0759
      14
      WET solvent suppression and its applications to LC NMR and high-resolution NMR spectroscopy
      Smallcombe, Stephen H.; Patt, Steven L.; Keifer, Paul A.
      Journal of Magnetic Resonance, Series A (1995), 117 (2), 295-303CODEN: JMRAE2; ISSN:1064-1858. (Academic)
      A review, with 29 refs., is given on recent developments on solvent suppression problems and their applications to liq. chromatog. with NMR detection.
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    15. 15
      Hwang, T. L.; Shaka, A. J. J. Magn. Reson., Ser. A 1995, 112, 275– 279 DOI: 10.1006/jmra.1995.1047
      15
      Water suppression that works. Excitation sculpting using arbitrary waveforms and pulsed field gradients
      Hwang, Tsang-Lin; Shaka, A. J.
      Journal of Magnetic Resonance, Series A (1995), 112 (2), 275-9CODEN: JMRAE2; ISSN:1064-1858. (Academic)
      A water suppression technique which can applied to most NMR expts. is described. A simple echo sequence employing a pulsed field gradient before and after the refocusing element is applied. Theor. background and examples are gives.
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    16. 16
      Liu, M.; Mao, X.-a.; Ye, C.; Huang, H.; Nicholson, J. K.; Lindon, J. C. J. Magn. Reson. 1998, 132, 125– 129 DOI: 10.1006/jmre.1998.1405
      16
      Improved WATERGATE pulse sequences for solvent suppression in NMR spectroscopy
      Liu, Maili; Mao, Xi-An; Ye, Chaohui; Huang, He; Nicholson, Jeremy K.; Lindon, John C.
      Journal of Magnetic Resonance (1998), 132 (1), 125-129CODEN: JMARF3; ISSN:1090-7807. (Academic Press)
      Modifications to the WATERGATE method for removing the solvent resonance from 1H NMR spectra are presented. In the conventional WATERGATE, a pulse train with three pairs of sym. pulses in the form 3α-τ-9α-τ-19α-τ-19α-τ-9α-τ-3α (designated here W3), where 26α = 180°, was used, while the improved versions use four and five pairs of sym. pulses (designated here W4 and W5), resp. The modified methods provide narrower noninversion regions and hence enhance the sensitivities of the peaks close to the H2O resonance. The inversion and suppression profiles of the pulse trains W3, W4, and W5 are compared theor. and exptl. and good agreement was obtained.
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    17. 17
      Piotto, M.; Saudek, V.; Sklenář, V. J. Biomol. NMR 1992, 2, 661– 665 DOI: 10.1007/BF02192855
      17
      Gradient-tailored excitation for single-quantum NMR spectroscopy of aqueous solutions
      Piotto, Martial; Saudek, Valdimir; Sklenar, Vladimir
      Journal of Biomolecular NMR (1992), 2 (6), 661-5CODEN: JBNME9; ISSN:0925-2738.
      A novel approach to tailored selective excitation for the measurement of NMR spectra in non-deuterated aq. solns. (WATERGATE, WATER suppression by GrAdient-Tailored Excitation) is described. The gradient echo sequence, which effectively combines one selective 180° radiofrequency pulse and two field gradient pulses, achieves highly selective and effective water suppression. This technique is ideally suited for the rapid collection of multi-dimensional data since a single-scan acquisition produces a pure phase NMR spectrum with a perfectly flat baseline, at the highest possible sensitivity. Application to the fast measurement of 2D NOE data of a 2.2. mM soln. of a double-stranded DNA fragment in 90% H2O at 5° is presented.
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    18. 18
      Sklenar, V.; Piotto, M.; Leppik, R.; Saudek, V. J. Magn. Reson., Ser. A 1993, 102, 241– 245 DOI: 10.1006/jmra.1993.1098
      18
      Gradient-tailored water suppression for proton-nitrogen-15 HSQC experiments optimized to retain full sensitivity
      Sklenar, Vladimir; Piotto, Martial; Leppik, Raymond; Saudek, Vladimir
      Journal of Magnetic Resonance, Series A (1993), 102 (2), 241-5CODEN: JMRAE2; ISSN:1064-1858.
      The authors demonstrate that a new tailored excitation scheme for efficient water suppression can be incorporated into phase-sensitive multidimensional NMR expts. with a heteronuclear single-quantum coherence (HSQC) step. This approach allows the carrier to be placed in the center of a protein amide region to maximize the digital resoln. in the acquisition domain. The gradient pulses are applied to suppress the water signal and signals of protons not coupled to 15N nuclei. The pulse schemes for the phase-sensitive 2D HSQC and 3D NOESY-HSQC expts. are diagrammed. Illustrative results are presented for a 1 mM sample of a uniformly 15N-labeled fragment of the transcriptional activator Jun in 90% H2O/10% D2O.
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    19. 19
      Simpson, A. J.; Brown, S. A. J. Magn. Reson. 2005, 175, 340– 346 DOI: 10.1016/j.jmr.2005.05.008
      There is no corresponding record for this reference.
    20. 20
      Giraudeau, P.; Silvestre, V.; Akoka, S. Metabolomics 2015, 11, 1041– 1055 DOI: 10.1007/s11306-015-0794-7
      There is no corresponding record for this reference.
    21. 21
      Mo, H.; Raftery, D. J. Magn. Reson. 2008, 190, 1– 6 DOI: 10.1016/j.jmr.2007.09.016
      21
      Pre-SAT180, a simple and effective method for residual water suppression
      Mo, Huaping; Raftery, Daniel
      Journal of Magnetic Resonance (2008), 190 (1), 1-6CODEN: JMARF3; ISSN:1090-7807. (Elsevier)
      Water located outside the NMR detection coil experiences a reduced RF field intensity. This "faraway water" is known to be very difficult to suppress and often gives rise to a large residual solvent signal. Pre-SAT180 (Pre-Satn. with Adiabatic Toggling of 180 degree pulse inversion) is proposed to cancel the residual water contribution efficiently. Compared with several popular methods such as 1D NOESY with pre-satn. or 270° excitation, Pre-SAT180 has a no. of advantages, including: full retention of signal intensity and selectivity, good phase properties, easy setup, and high tolerance to pulse missettings.
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    22. 22
      Mo, H.; Raftery, D. J. Biomol. NMR 2008, 41, 105– 111 DOI: 10.1007/s10858-008-9246-2
      There is no corresponding record for this reference.
    23. 23
      McKelvie, J. R.; Yuk, J.; Xu, Y.; Simpson, A. J.; Simpson, M. J. Metabolomics 2009, 5, 84 DOI: 10.1007/s11306-008-0122-6
      There is no corresponding record for this reference.
    24. 24
      Brown, S. A. E.; Simpson, A. J.; Simpson, M. J. Environmental Chemistry 2009, 6, 432– 440 DOI: 10.1071/EN09054
      24
      1H NMR metabolomics of earthworm responses to sub-lethal PAH exposure
      Brown, Sarah A. E.; Simpson, Andre J.; Simpson, Myrna J.
      Environmental Chemistry (2009), 6 (5), 432-440CODEN: ECNHAA; ISSN:1449-8979. (CSIRO Publishing)
      Metabolic responses of earthworm exposure to the polycyclic arom. hydrocarbons (PAHs) naphthalene, phenanthrene and pyrene in contact tests were measured using 1H NMR. Novel metabolites were not detected but principal component anal. (PCA) showed that earthworms exposed to 10, 50, and 100 μg cm-2 naphthalene, phenanthrene and pyrene differed from unexposed (control) earthworms. Partial least-squares-discriminant anal. (PLS-DA) showed that earthworms had statistically significant responses to PAH exposure, except for 10 μg/cm-2 naphthalene and 50 μg/cm-2 pyrene. Leucine, valine, alanine, lysine, and maltose were identified as potential response indicators of PAH exposure, but whether the concn. of these metabolites increased or decreased was PAH- and concn.-dependent. These initial findings reveal the potential of metabolomics for monitoring earthworm responses to sub-lethal PAH exposure and highlight the role of metabolomics as a future tool in ecotoxicol.
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    25. 25
      Brown, S. A. E.; McKelvie, J. R.; Simpson, A. J.; Simpson, M. J. Environ. Pollut. 2010, 158, 2117– 2123 DOI: 10.1016/j.envpol.2010.02.023
      There is no corresponding record for this reference.
    26. 26
      Whitfield Åslund, M. L.; Simpson, A. J.; Simpson, M. J. Ecotoxicology 2011, 20, 836– 846 DOI: 10.1007/s10646-011-0638-9
      There is no corresponding record for this reference.
    27. 27
      Woods, G. C.; Simpson, M. J.; Koerner, P. J.; Napoli, A.; Simpson, A. J. Environ. Sci. Technol. 2011, 45, 3880– 3886 DOI: 10.1021/es103425s
      There is no corresponding record for this reference.
    28. 28
      Whitfield Åslund, M.; Simpson, M. J.; Simpson, A. J.; Zeeb, B. A.; Rutter, A. Ecotoxicology 2012, 21, 1947– 1956 DOI: 10.1007/s10646-012-0928-x
      There is no corresponding record for this reference.
    29. 29
      Lankadurai, B.; Furdui, V.; Reiner, E.; Simpson, A.; Simpson, M. Metabolites 2013, 3, 718 DOI: 10.3390/metabo3030718
      There is no corresponding record for this reference.
    30. 30
      Lankadurai, B. P.; Wolfe, D. M.; Whitfield Åslund, M. L.; Simpson, A. J.; Simpson, M. J. Metabolomics 2013, 9, 44– 56 DOI: 10.1007/s11306-012-0427-3
      There is no corresponding record for this reference.
    31. 31
      Lankadurai, B. P.; Nagato, E. G.; Simpson, A. J.; Simpson, M. J. Ecotoxicol. Environ. Saf. 2015, 120, 48– 58 DOI: 10.1016/j.ecoenv.2015.05.020
      There is no corresponding record for this reference.
    32. 32
      Marshall, M. H. M.; McKelvie, J. R.; Simpson, A. J.; Simpson, M. J. Appl. Geochem. 2015, 54, 43– 53 DOI: 10.1016/j.apgeochem.2014.12.013
      32
      Characterization of natural organic matter in bentonite clays for potential use in deep geological repositories for used nuclear fuel
      Marshall, Michaela H. M.; McKelvie, Jennifer R.; Simpson, Andre J.; Simpson, Myrna J.
      Applied Geochemistry (2015), 54 (), 43-53CODEN: APPGEY; ISSN:0883-2927. (Elsevier Ltd.)
      The Nuclear Waste Management Organization (NWMO) is developing a Deep Geol. Repository (DGR) to contain and isolate used nuclear fuel in a suitable rock formation at a depth of approx. 500 m. The design concept employs a multibarrier system, including the use of copper-coated used fuel containers, surrounded by a low-permeability, swelling clay buffer material within a low permeability, stable host rock environment. The natural org. matter (NOM) compn. of the bentonite clays being considered for the buffer material is largely uncharacterized at the mol.-level. To gain a better understanding of the NOM in target clays from Wyoming and Saskatchewan, mol.-level methods (biomarker anal., solid-state 13C NMR and soln.-state 1H NMR (NMR)) were used to elucidate the structure and sources of NOM. Org. carbon content in three com. available bentonites analyzed was low (0.11-0.41%). The aliph. lipid distribution of the clay samples analyzed showed a predominance of higher concn. of lipids from vascular plants and low concns. of lipids consistent with microbial origin. The lignin phenol vanillyl acid to aldehyde ratio (Ad/Al) for the National sample indicated an advanced state of lignin oxidn. and NOM diagenesis. The 13C NMR spectra were dominated by signals in the arom. and aliph. regions. The ratio of alkyl/O-alkyl carbon ranged from 7.6 to 9.7, indicating that the NOM has undergone advanced diagenetic alteration. The absence lignin-derived phenols commonly obsd. in CuO oxidn. exts. from contemporary soils and sediments as well as the lack of amino acids suggests that the material corresponding to the arom. signal is not composed of lignin or proteins but may be derived from another source such as black carbon or some other non-extractable arom.-rich NOM. The aliph. signal appears to correspond to long-chain compds. with little side branching based on the results of the one-dimensional (1D) and two-dimensional (2D) soln.-state 1H NMR analyses. Overall, the org. geochem. analyses suggest that the NOM is composed mainly of plant-derived waxes and highly arom. carbon with low contributions from small mols. The compds. identified by the mol.-level anal. of NOM in the clay samples are hypothesized to be recalcitrant but future studies should examine if these compds. may serve as a microbial substrate to further test the observations of this study. Furthermore, our study suggests that the NOM has undergone diagenesis and that marine NOM signatures are no longer recognizable or detectable. As such, future work may also examine the diagenesis of these deposits to further understand the NOM geochem. and paleoenvironmental conditions in bentonite deposits.
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    33. 33
      Kovacevic, V.; Simpson, A. J.; Simpson, M. J. Comp. Biochem. Physiol., Part D: Genomics Proteomics 2016, 19, 199– 210 DOI: 10.1016/j.cbd.2016.01.004
      33
      1H NMR-based metabolomics of Daphnia magna responses after sub-lethal exposure to triclosan, carbamazepine and ibuprofen
      Kovacevic, Vera; Simpson, Andre J.; Simpson, Myrna J.
      Comparative Biochemistry and Physiology, Part D: Genomics & Proteomics (2016), 19 (), 199-210CODEN: CBPPBG; ISSN:1744-117X. (Elsevier B.V.)
      Pharmaceuticals and personal care products are a class of emerging contaminants that are present in wastewater effluents, surface water, and groundwater around the world. There is a need to det. rapid and reliable bioindicators of exposure and the toxic mode of action of these contaminants to aquatic organisms. 1H NMR (NMR)-based metabolomics in combination with multivariate statistical anal. was used to det. the metabolic profile of Daphnia magna after exposure to a range of sub-lethal concns. of triclosan (6.25-100 μg/L), carbamazepine (1.75-14 mg/L) and ibuprofen (1.75-14 mg/L) for 48 h. Sub-lethal triclosan exposure suggested a general oxidative stress condition and the branched-chain amino acids, glutamine, glutamate, and methionine emerged as potential bioindicators. The arom. amino acids, serine, glycine and alanine are potential bioindicators for sub-lethal carbamazepine exposure that may have altered energy metab. The potential bioindicators for sub-lethal ibuprofen exposure are serine, methionine, lysine, arginine and leucine, which showed a concn.-dependent response. The differences in the metabolic changes were related to the dissimilar modes of toxicity of triclosan, carbamazepine and ibuprofen. 1H NMR-based metabolomics gave an improved understanding of how these emerging contaminants impact the keystone species D. magna.
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    34. 34
      Nagato, E. G.; Simpson, A. J.; Simpson, M. J. Aquat. Toxicol. 2016, 170, 175– 186 DOI: 10.1016/j.aquatox.2015.11.023
      34
      Metabolomics reveals energetic impairments in Daphnia magna exposed to diazinon, malathion and bisphenol-A
      Nagato, Edward G.; Simpson, Andre J.; Simpson, Myrna J.
      Aquatic Toxicology (2016), 170 (), 175-186CODEN: AQTODG; ISSN:0166-445X. (Elsevier B.V.)
      1H NMR (NMR)-based metabolomics was used to study the response of Daphnia magna to increasing sub-lethal concns. of either an organophosphate (diazinon or malathion) or bisphenol-A (BPA). Principal component anal. (PCA) of 1H NMR spectra were used to screen metabolome changes after 48 h of contaminant exposure. The PCA scores plots showed that diazinon exposures resulted in aberrant metabolomic profiles at all exposure concns. tested (0.009-0.135 μg/L), while for malathion the second lowest (0.08 μg/L) and two highest exposure concns. (0.32 μg/L and 0.47 μg/L) caused significant shifts from the control. Individual metabolite changes for both organophosphates indicated that the response to increasing exposure was non-linear and described perturbations in the metabolome that were characteristic of the severity of exposure. For example, intermediate concns. of diazinon (0.045 μg/L and 0.09 μg/L) and malathion (0.08 μg/L) elicited a decrease in amino acids such as leucine, valine, arginine, glycine, lysine, glutamate, glutamine, phenylalanine and tyrosine, with concurrent increases in glucose and lactate, suggesting a mobilization of energy resources to combat stress. At the highest exposure concns. for both organophosphates there was evidence of a cessation in metabolic activity, where the same amino acids increased and glucose and lactate decreased, suggesting a slowdown in protein synthesis and depletion of energy stocks. This demonstrated a similar response in the metabolome between two organophosphates but also that intermediate and severe stress levels could be differentiated by changes in the metabolome. For BPA exposures, the PCA scores plot showed a significant change in metabolome at 0.1 mg/L, 1.4 mg/L and 2.1 mg/L of exposure. Individual metabolite changes from 0.7 to 2.1 mg/L of BPA exposure showed increases in amino acids such as alanine, valine, isoleucine, leucine, arginine, phenylalanine and tyrosine. These metabolite changes were correlated with decreases in glucose and lactate. This pattern of response was also seen in the highest organophosphate exposures and suggested a generalized stress response that could be related to altered energy dynamics in D. magna. Through studying increasing exposure responses, we have demonstrated the ability of metabolomics to identify discrete differences between intermediate and severe stress, and also to characterize how systemic stress is manifested in the metabolome.
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    35. 35
      Wagner, N. D.; Simpson, A. J.; Simpson, M. J. Environ. Toxicol. Chem. 2017, 36, 938– 946 DOI: 10.1002/etc.3604
      There is no corresponding record for this reference.
    36. 36
      Hölscher, D.; Brand, S.; Wenzler, M.; Schneider, B. J. Nat. Prod. 2008, 71, 251– 257 DOI: 10.1021/np0705514
      There is no corresponding record for this reference.
    37. 37
      Byrne, C. M. P.; Hayes, M. H. B.; Kumar, R.; Novotny, E. H.; Lanigan, G.; Richards, K. G.; Fay, D.; Simpson, A. J. Water Res. 2010, 44, 4379– 4390 DOI: 10.1016/j.watres.2010.05.055
      There is no corresponding record for this reference.
    38. 38
      Lesar, C. T.; Decatur, J.; Lukasiewicz, E.; Champeil, E. Forensic Sci. Int. 2011, 212, e40– e45 DOI: 10.1016/j.forsciint.2011.06.017
      38
      Report on the analysis of common beverages spiked with gamma-hydroxybutyric acid (GHB) and gamma-butyrolactone (GBL) using NMR and the PURGE solvent-suppression technique
      Lesar, Casey T.; Decatur, John; Lukasiewicz, Elaan; Champeil, Elise
      Forensic Science International (2011), 212 (1-3), e40-e45CODEN: FSINDR; ISSN:0379-0738. (Elsevier Ltd.)
      In forensic evidence, the identification and quantitation of gamma-hydroxybutyric acid (GHB) in "spiked" beverages is challenging. In this report, we present the anal. of common alc. beverages found in clubs and bars spiked with gamma-hydroxybutyric acid (GHB) and gamma-butyrolactone (GBL). Our anal. of the spiked beverages consisted of using 1H NMR with a water suppression method called Presatn. Utilizing Relaxation Gradients and Echoes (PURGE). The following beverages were analyzed: water, 10% ethanol in water, vodka-cranberry juice, rum and coke, gin and tonic, whisky and diet coke, white wine, red wine, and beer. The PURGE method allowed for the direct identification and quantitation of both compds. in all beverages except red and white wine where small interferences prevented accurate quantitation. The NMR method presented in this paper utilizes PURGE water suppression. Thanks to the use of a capillary internal std., the method is fast, non-destructive, sensitive and requires no sample prepn. which could disrupt the equil. between GHB and GBL.
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    39. 39
      Houghton, J. L.; Biswas, T.; Chen, W.; Tsodikov, O. V.; Garneau-Tsodikova, S. ChemBioChem 2013, 14, 2127– 2135 DOI: 10.1002/cbic.201300359
      There is no corresponding record for this reference.
    40. 40
      Houghton, J. L.; Green, K. D.; Pricer, R. E.; Mayhoub, A. S.; Garneau-Tsodikova, S. J. Antimicrob. Chemother. 2013, 68, 800– 805 DOI: 10.1093/jac/dks497
      40
      Unexpected N-acetylation of capreomycin by mycobacterial Eis enzymes
      Houghton, Jacob L.; Green, Keith D.; Pricer, Rachel E.; Mayhoub, Abdelrahman S.; Garneau-Tsodikova, Sylvie
      Journal of Antimicrobial Chemotherapy (2013), 68 (4), 800-805CODEN: JACHDX; ISSN:0305-7453. (Oxford University Press)
      The enhanced intracellular survival (Eis) protein from Mycobacterium tuberculosis (EisMtb), a regio-versatile N-acetyltransferase active towards many aminoglycosides (AGs), confers resistance to kanamycin A in some cases of extensively drug-resistant tuberculosis (XDR-TB). We assessed the activity of EisMtb and of its homolog from Mycobacterium smegmatis (EisMsm) against a panel of anti-tuberculosis (TB) drugs and lysine-contg. compds. Both enzymes acetylated capreomycin and some lysine-contg. compds., but not other non-AG non-lysine-contg. drugs tested. Modeling studies predicted the site of modification on capreomycin to be one of the two primary amines in its β-lysine side chain. Using EisMtb, we established via NMR spectroscopy that acetylation of capreomycin occurs on the ε-amine of the β-lysine side chain. Using Msm, we also demonstrated for the first time to our knowledge that acetylation of capreomycin results in deactivation of the drug. Eis is a unique acetyltransferase capable of inactivating the anti-TB drug capreomycin, AGs and other lysine-contg. compds.
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    41. 41
      Pardo Torre, J. C.; Schmidt, G. W.; Paetz, C.; Reichelt, M.; Schneider, B.; Gershenzon, J.; D’Auria, J. C. Phytochemistry 2013, 91, 177– 186 DOI: 10.1016/j.phytochem.2012.09.009
      There is no corresponding record for this reference.
    42. 42
      Plaza, C.; Courtier-Murias, D.; Fernández, J. M.; Polo, A.; Simpson, A. J. Soil Biol. Biochem. 2013, 57, 124– 134 DOI: 10.1016/j.soilbio.2012.07.026
      42
      Physical, chemical, and biochemical mechanisms of soil organic matter stabilization under conservation tillage systems: A central role for microbes and microbial by-products in C sequestration
      Plaza, Cesar; Courtier-Murias, Denis; Fernandez, Jose M.; Polo, Alfredo; Simpson, Andre J.
      Soil Biology & Biochemistry (2013), 57 (), 124-134CODEN: SBIOAH; ISSN:0038-0717. (Elsevier B.V.)
      Conservation tillage practices that entail no or reduced soil disturbance are known to help preserve or accumulate soil org. matter (OM). However, the underlying mechanisms esp. at the mol. level are not well understood. In this study soil samples from 25-yr-old exptl. plots continuously cropped with barley (Hordeum vulgare L.) under no-tillage (NT) and chisel tillage (CT) were subjected to a new phys. fractionation method to isolate dissolved OM, mineral-free particulate OM located outside aggregates (phys. and chem. unprotected), OM occluded within both macroaggregates and microaggregates (weakly and strongly protected by phys. mechanisms, resp.), and OM in intimate assocn. with minerals (protected by chem. mechanisms). The whole soils and OM fractions were analyzed for org. C and N content and by modern NMR techniques. The soil under NT stored 16% more org. C and 5% more N than the soil under CT. Compared to CT, NT increased free org. C content by 7%, intra-macroaggregate org. C content by 20%, intra-microaggregate org. C content by 63%, and mineral-assocd. org. C content by 16% and decreased dissolved org. C content by 11%. The mineral-assocd. OM pool accounted for 65% of the difference in total org. C content between NT and CT, whereas the intra-microaggregate OM only explained 18%, intra-macroaggregate OM 14%, and free OM 11%. The NMR expts. revealed that the free and intra-aggregate OM fractions were dominated by crop-derived materials at different stages of decompn., whereas the mineral-assocd. OM pool was predominately of microbial origin. Overall, our results indicate that microbes and microbial byproducts assocd. with mineral surfaces and likely phys. protected by entrapment within very small microaggregates constitute the most important pool of OM stabilization and C sequestration in soils under NT. Most probably the slower macroaggregate turnover in NT relative to CT boosts not only the formation of microaggregates and thereby the phys. protection of crop-derived particulate OM, but more importantly the interaction between mineral particles and microbial material that results in the formation of very stable organo-mineral complexes.
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    43. 43
      Koehler, J.; Beck Erlach, M.; Crusca, E.; Kremer, W.; Munte, C. E.; Meier, A.; Kalbitzer, H. R. J. Biomol. NMR 2014, 60, 45– 50 DOI: 10.1007/s10858-014-9850-2
      There is no corresponding record for this reference.
    44. 44
      del Campo, G.; Zuriarrain, J.; Zuriarrain, A.; Berregi, I. Food Chem. 2016, 196, 1031– 1039 DOI: 10.1016/j.foodchem.2015.10.036
      There is no corresponding record for this reference.
    45. 45
      Marshall, D. D.; Sadykov, M. R.; Thomas, V. C.; Bayles, K. W.; Powers, R. J. Proteome Res. 2016, 15, 1205– 1212 DOI: 10.1021/acs.jproteome.5b01089
      45
      Redox Imbalance Underlies the Fitness Defect Associated with Inactivation of the Pta-AckA Pathway in Staphylococcus aureus
      Marshall, Darrell D.; Sadykov, Marat R.; Thomas, Vinai C.; Bayles, Kenneth W.; Powers, Robert
      Journal of Proteome Research (2016), 15 (4), 1205-1212CODEN: JPROBS; ISSN:1535-3893. (American Chemical Society)
      The phosphotransacetylase-acetate kinase (Pta-AckA) pathway is thought to be a vital ATP generating pathway for Staphylococcus aureus. Disruption of the Pta-AckA pathway during overflow metab. causes significant redn. in growth rate and viability, albeit not due to intracellular ATP depletion. Here, we demonstrate that toxicity assocd. with inactivation of the Pta-AckA pathway resulted from an altered intracellular redox environment. Growth of the pta and ackA mutants under anaerobic conditions partially restored cell viability. NMR metabolomics analyses and 13C6-glucose metab. tracing expts. revealed the activity of multiple pathways that promote redox (NADH/NAD+) turnover to be enhanced in the pta and ackA mutants during anaerobic growth. Restoration of redox homeostasis in the pta mutant by overexpressing L- lactate dehydrogenase partially restored its viability under aerobic conditions. Together, our findings suggest that during overflow metab., the Pta-AckA pathway plays a crit. role in preventing cell viability defects by promoting intracellular redox homeostasis.
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    46. 46
      Vučković, I.; Rapinoja, M.-L.; Vaismaa, M.; Vanninen, P.; Koskela, H. Phytochem. Anal. 2016, 27, 64– 72 DOI: 10.1002/pca.2600
      46
      Application of comprehensive NMR-based analysis strategy in annotation, isolation and structure elucidation of low molecular weight metabolites of Ricinus communis seeds
      Vuckovic, Ivan; Rapinoja, Marja-Leena; Vaismaa, Matti; Vanninen, Paula; Koskela, Harri
      Phytochemical Analysis (2016), 27 (1), 64-72CODEN: PHANEL; ISSN:0958-0344. (John Wiley & Sons Ltd.)
      Introduction : Powder-like ext. of Ricinus communis seeds contain a toxic protein, ricin, which has a history of military, criminal and terroristic use. As the detection of ricin in this "terrorist powder" is difficult and time-consuming, related low mass metabolites have been suggested to be useful for screening as biomarkers of ricin. Objective : To apply a comprehensive NMR-based anal. strategy for annotation, isolation and structure elucidation of low mol. wt. plant metabolites of Ricinus communis seeds. Methodol. : The seed ext. was prepd. with a well-known acetone extn. approach. The common metabolites were annotated from seed ext. dissolved in acidic soln. using 1H NMR spectroscopy with spectrum library comparison and std. addn., whereas unconfirmed metabolites were identified using multi-step off-line HPLC-DAD-NMR approach. Results : In addn. to the common plant metabolites, two previously unreported compds., 1,3-digalactoinositol and ricinyl-alanine, were identified with support of MS analyses. Conclusion : The applied comprehensive NMR-based anal. strategy provided identification of the prominent low mol. wt. metabolites with high confidence. Copyright © 2015 John Wiley & Sons, Ltd.
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    47. 47
      Kim, H. K.; Choi, Y. H.; Verpoorte, R. Nat. Protoc. 2010, 5, 536– 549 DOI: 10.1038/nprot.2009.237
      47
      NMR-based metabolomic analysis of plants
      Kim, Hye Kyong; Choi, Young Hae; Verpoorte, Robert
      Nature Protocols (2010), 5 (3), 536-549CODEN: NPARDW; ISSN:1750-2799. (Nature Publishing Group)
      NMR-based metabolomics has many applications in plant science. Metabolomics can be used in functional genomics and to differentiate plants from different origin, or after different treatments. In this protocol, the following steps of plant metabolomics using NMR spectroscopy are described: sample prepn. (freeze drying followed by extn. by ultrasonication with 1:1 CD3OD:KH2PO4 buffer in D2O), NMR anal. (std. 1H, J-resolved, 1H-1H correlation spectroscopy (COSY) and heteronuclear multiple bond correlation (HMBC)) and chemometric methods. The main advantage of NMR metabolomic anal. is the possibility of identifying metabolites by comparing NMR data with refs. or by structure elucidation using two-dimensional NMR. This protocol is particularly suited for the anal. of secondary metabolites such as phenolic compds. (usually abundant in plants), and for primary metabolites (e.g., sugars and amino acids). This procedure is rapid; it takes no more than 30 min for sample prepn. (multiple parallel) and a further 10 min for NMR spectrum acquisition.
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    48. 48
      Aguilar, J. A.; Kenwright, S. J. Analyst 2016, 141, 236– 242 DOI: 10.1039/C5AN02121A
      There is no corresponding record for this reference.
    49. 49
      Aguilar, J. A.; Nilsson, M.; Bodenhausen, G.; Morris, G. A. Chem. Commun. 2012, 48, 811– 813 DOI: 10.1039/C1CC16699A
      49
      Spin echo NMR spectra without J modulation
      Aguilar, Juan A.; Nilsson, Mathias; Bodenhausen, Geoffrey; Morris, Gareth A.
      Chemical Communications (Cambridge, United Kingdom) (2012), 48 (6), 811-813CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
      The spin echo is the single most important building block in modern NMR spectroscopy, but echo modulation by scalar couplings J can severely complicate its use. We show for the first time that a general but unacknowledged soln. to such complications already exists.
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    50. 50
      Takegoshi, K.; Ogura, K.; Hikichi, K. J. Magn. Reson. (1969-1992) 1989, 84, 611– 615 DOI: 10.1016/0022-2364(89)90127-3
      There is no corresponding record for this reference.
    51. 51
      Leung, I. K. H.; Demetriades, M.; Hardy, A. P.; Lejeune, C.; Smart, T. J.; Szöllössi, A.; Kawamura, A.; Schofield, C. J.; Claridge, T. D. W. J. Med. Chem. 2013, 56, 547– 555 DOI: 10.1021/jm301583m
      There is no corresponding record for this reference.
    52. 52
      Pinto, L. F.; Riguera, R.; Fernandez-Megia, E. J. Am. Chem. Soc. 2013, 135, 11513– 11516 DOI: 10.1021/ja4059348
      There is no corresponding record for this reference.
    53. 53
      Sánchez-Fernández, E. M.; Tarhonskaya, H.; Al-Qahtani, K.; Hopkinson; Richard, J.; McCullagh; James, S. O.; Schofield; Christopher, J.; Flashman, E. Biochem. J. 2013, 449, 491– 496 DOI: 10.1042/BJ20121155
      There is no corresponding record for this reference.
    54. 54
      André, M.; Dumez, J.-N.; Rezig, L.; Shintu, L.; Piotto, M.; Caldarelli, S. Anal. Chem. 2014, 86, 10749– 10754 DOI: 10.1021/ac502792u
      There is no corresponding record for this reference.
    55. 55
      Castañar, L.; Nolis, P.; Virgili, A.; Parella, T. J. Magn. Reson. 2014, 244, 30– 35 DOI: 10.1016/j.jmr.2014.04.003
      There is no corresponding record for this reference.
    56. 56
      Walport, L. J.; Hopkinson, R. J.; Vollmar, M.; Madden, S. K.; Gileadi, C.; Oppermann, U.; Schofield, C. J.; Johansson, C. J. Biol. Chem. 2014, 289, 18302– 18313 DOI: 10.1074/jbc.M114.555052
      There is no corresponding record for this reference.
    57. 57
      Berman, P.; Meiri, N.; Colnago, L. A.; Moraes, T. B.; Linder, C.; Levi, O.; Parmet, Y.; Saunders, M.; Wiesman, Z. Biotechnol. Biofuels 2015, 8, 12 DOI: 10.1186/s13068-014-0194-7
      57
      Study of liquid-phase molecular packing interactions and morphology of fatty acid methyl esters (biodiesel)
      Berman, Paula; Meiri, Nitzan; Colnago, Luiz Alberto; Moraes, Tiago Bueno; Linder, Charles; Levi, Ofer; Parmet, Yisrael; Saunders, Michael; Wiesman, Zeev
      Biotechnology for Biofuels (2015), 8 (), 12/1-12/16CODEN: BBIIFL; ISSN:1754-6834. (BioMed Central Ltd.)
      Background:1H low field NMR (LF-NMR) relaxometry has been suggested as a tool to distinguish between different mol. ensembles in complex systems with differential segmental or whole mol. motion and/or different morphologies. In biodiesel applications the mol. structure vs. liq.-phase packing morphologies of fatty acid Me esters (FAMEs) influences physico-chem. characteristics of the fuel, including flow properties, operability during cold weather, blending, and more. Still, their liq. morphol. structures have scarcely been studied. It was therefore the objective of this work to explore the potential of this technol. for characterizing the mol. organization of FAMEs in the liq. phase. This was accomplished by using a combination of supporting advanced technologies. Results:We show that pure oleic acid (OA) and Me oleate (MO) stds. exhibited both similarities and differences in the 1H LF-NMR relaxation times (T2s) and peak areas, for a range of temps. Based on X-ray measurements, both mols. were found to possess a liq. crystal-like order, although a larger fluidity was found for MO, because as the temp. is increased, MO mols. sep. both longitudinally and transversely from one another. In addn., both mols. exhibited a preferred direction of diffusion based on the apparent hydrodynamic radius. The close mol. packing arrangement and interactions were found to affect the translational and segmental motions of the mols., as a result of dimerization of the head group in OA as opposed to weaker polar interactions in MO. Conclusions:Acomprehensive model for the liq. crystal-like arrangement of FAMEs in the liq. phase is suggested. The differences in translational and segmental motions of the mols. were rationalized by the differences in the 1H LF-NMR T2 distributions of OA and MO, which was further supported by 13C high field (HF)-NMR spectra and 1H HF-NMR relaxation. The proposed assignment allows for material characterization based on parameters that contribute to properties in applications such as biodiesel fuels.
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    58. 58
      Klika, K. D. Org. Lett. 2012, 14, 524– 527 DOI: 10.1021/ol2031334
      There is no corresponding record for this reference.
    59. 59
      Adams, R. W.; Holroyd, C. M.; Aguilar, J. A.; Nilsson, M.; Morris, G. A. Chem. Commun. 2013, 49, 358– 360 DOI: 10.1039/C2CC37579F
      59
      "Perfecting" WATERGATE: clean proton NMR spectra from aqueous solution
      Adams, Ralph W.; Holroyd, Chloe M.; Aguilar, Juan A.; Nilsson, Mathias; Morris, Gareth A.
      Chemical Communications (Cambridge, United Kingdom) (2013), 49 (4), 358-360CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
      A simple modification of the WATERGATE solvent suppression method greatly improves the quality of 1H NMR spectra obtainable from samples in H2O. The new method allows 1H signals to be measured even when close in chem. shift to the signal of H2O, as e.g. in the NMR spectra of carbohydrates.
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    60. 60
      Baishya, B.; Khetrapal, C. L.; Dey, K. K. J. Magn. Reson. 2013, 234, 67– 74 DOI: 10.1016/j.jmr.2013.06.004
      There is no corresponding record for this reference.
    61. 61
      Gambarota, G.; Bondon, A.; Floch, M. L.; Mulkern, R. V.; Saint-Jalmes, H. J. Magn. Reson. 2013, 228, 76– 80 DOI: 10.1016/j.jmr.2012.12.014
      There is no corresponding record for this reference.
    62. 62
      Baishya, B.; Khetrapal, C. L. J. Magn. Reson. 2014, 242, 143– 154 DOI: 10.1016/j.jmr.2014.02.017
      There is no corresponding record for this reference.
    63. 63
      Kaltschnee, L.; Kolmer, A.; Timari, I.; Schmidts, V.; Adams, R. W.; Nilsson, M.; Kover, K. E.; Morris, G. A.; Thiele, C. M. Chem. Commun. 2014, 50, 15702– 15705 DOI: 10.1039/C4CC04217D
      There is no corresponding record for this reference.
    64. 64
      Baishya, B.; Verma, A. J. Magn. Reson. 2015, 252, 41– 48 DOI: 10.1016/j.jmr.2014.12.007
      There is no corresponding record for this reference.
    65. 65
      Aguilar, J. A.; Adams, R. W.; Nilsson, M.; Morris, G. A. J. Magn. Reson. 2014, 238, 16– 19 DOI: 10.1016/j.jmr.2013.10.018
      There is no corresponding record for this reference.
    66. 66
      Gowda, G. A. N.; Raftery, D. Anal. Chem. 2014, 86, 5433– 5440 DOI: 10.1021/ac5005103
      There is no corresponding record for this reference.
    67. 67
      Nagana Gowda, G. A.; Gowda, Y. N.; Raftery, D. Anal. Chem. 2015, 87, 706– 715 DOI: 10.1021/ac503651e
      There is no corresponding record for this reference.
    68. 68
      Soininen, P.; Kangas, A. J.; Wurtz, P.; Tukiainen, T.; Tynkkynen, T.; Laatikainen, R.; Jarvelin, M.-R.; Kahonen, M.; Lehtimaki, T.; Viikari, J.; Raitakari, O. T.; Savolainen, M. J.; Ala-Korpela, M. Analyst 2009, 134, 1781– 1785 DOI: 10.1039/b910205a
      There is no corresponding record for this reference.
    69. 69
      Kaess, B. M.; Tomaszewski, M.; Braund, P. S.; Stark, K.; Rafelt, S.; Fischer, M.; Hardwick, R.; Nelson, C. P.; Debiec, R.; Huber, F.; Kremer, W.; Kalbitzer, H. R.; Rose, L. M.; Chasman, D. I.; Hopewell, J.; Clarke, R.; Burton, P. R.; Tobin, M. D.; Hengstenberg, C.; Samani, N. J. PLoS One 2011, 6, e14529 DOI: 10.1371/journal.pone.0014529
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      Petersen, A.-K.; Stark, K.; Musameh, M. D.; Nelson, C. P.; Römisch-Margl, W.; Kremer, W.; Raffler, J.; Krug, S.; Skurk, T.; Rist, M. J.; Daniel, H.; Hauner, H.; Adamski, J.; Tomaszewski, M.; Döring, A.; Peters, A.; Wichmann, H. E.; Kaess, B. M.; Kalbitzer, H. R.; Huber, F.; Pfahlert, V.; Samani, N. J.; Kronenberg, F.; Dieplinger, H.; Illig, T.; Hengstenberg, C.; Suhre, K.; Gieger, C.; Kastenmüller, G. Hum. Mol. Genet. 2012, 21, 1433– 1443 DOI: 10.1093/hmg/ddr580
      70
      Genetic associations with lipoprotein subfractions provide information on their biological nature
      Petersen, Ann-Kristin; Stark, Klaus; Musameh, Muntaser D.; Nelson, Christopher P.; Roemisch-Margl, Werner; Kremer, Werner; Raffler, Johannes; Krug, Susanne; Skurk, Thomas; Rist, Manuela J.; Daniel, Hannelore; Hauner, Hans; Adamski, Jerzy; Tomaszewski, Maciej; Doering, Angela; Peters, Annette; Wichmann, H.-Erich; Kaess, Bernhard M.; Kalbitzer, Hans Robert; Huber, Fritz; Pfahlert, Volker; Samani, Nilesh J.; Kronenberg, Florian; Dieplinger, Hans; Illig, Thomas; Hengstenberg, Christian; Suhre, Karsten; Gieger, Christian; Kastenmueller, Gabi
      Human Molecular Genetics (2012), 21 (6), 1433-1443CODEN: HMGEE5; ISSN:0964-6906. (Oxford University Press)
      Adverse levels of lipoproteins are highly heritable and constitute risk factors for cardiovascular outcomes. Hitherto, genome-wide assocn. studies revealed 95 lipid-assocd. loci. However, due to the small effect sizes of these assocns. large sample nos. (>100,000 samples) were needed. Here we show that analyzing more refined lipid phenotypes, namely lipoprotein subfractions, can increase the no. of significantly assocd. loci compared with bulk high-d. lipoprotein and low-d. lipoprotein anal. in a study with identical sample nos. Moreover, lipoprotein subfractions provide novel insight into the human lipid metab. We measured 15 lipoprotein subfractions (L1-L15) in 1791 samples using 1H-NMR spectroscopy. Using cluster analyses, we quantified inter-relationships among lipoprotein subfractions. Addnl., we analyzed assocns. with subfractions at known lipid loci. We identified five distinct groups of subfractions: one (L1) was only marginally captured by serum lipids and therefore extends our knowledge of lipoprotein biochem. During a lipid-tolerance test, L1 lost its special position. In the assocn. anal., we found that eight loci (LIPC, CETP, PLTP, FADS1-2-3, SORT1, GCKR, APOB, APOA1) were assocd. with the subfractions, whereas only four loci (CETP, SORT1, GCKR, APOA1) were assocd. with serum lipids. For LIPC, we obsd. a 10-fold increase in the variance explained by our regression models. In conclusion, NMR-based fine mapping of lipoprotein subfractions provides novel information on their biol. nature and strengthens the assocns. with genetic loci. Future clin. studies are now needed to investigate their biomedical relevance.
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    71. 71
      Dashti, H.; Westler, W. M.; Markley, J. L.; Eghbalnia, H. R. Sci. Data 2017, 4, 170073 DOI: 10.1038/sdata.2017.73
      71
      Unique identifiers for small molecules enable rigorous labeling of their atoms
      Dashti Hesam; Westler William M; Markley John L; Eghbalnia Hamid R
      Scientific data (2017), 4 (), 170073 ISSN:.
      Rigorous characterization of small organic molecules in terms of their structural and biological properties is vital to biomedical research. The three-dimensional structure of a molecule, its 'photo ID', is inefficient for searching and matching tasks. Instead, identifiers play a key role in accessing compound data. Unique and reproducible molecule and atom identifiers are required to ensure the correct cross-referencing of properties associated with compounds archived in databases. The best approach to this requirement is the International Chemical Identifier (InChI). However, the current implementation of InChI fails to provide a complete standard for atom nomenclature, and incorrect use of the InChI standard has resulted in the proliferation of non-unique identifiers. We propose a methodology and associated software tools, named ALATIS, that overcomes these shortcomings. ALATIS is an adaptation of InChI, which operates fully within the InChI convention to provide unique and reproducible molecule and all atom identifiers. ALATIS includes an InChI extension for unique atom labeling of symmetric molecules. ALATIS forms the basis for improving reproducibility and unifying cross-referencing across databases.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1cngtleisw%253D%253D&md5=5213ac7c61662f7d35b5080ad1801eda
    72. 72
      Phinney, K. W.; Ballihaut, G.; Bedner, M.; Benford, B. S.; Camara, J. E.; Christopher, S. J.; Davis, W. C.; Dodder, N. G.; Eppe, G.; Lang, B. E.; Long, S. E.; Lowenthal, M. S.; McGaw, E. A.; Murphy, K. E.; Nelson, B. C.; Prendergast, J. L.; Reiner, J. L.; Rimmer, C. A.; Sander, L. C.; Schantz, M. M.; Sharpless, K. E.; Sniegoski, L. T.; Tai, S. S. C.; Thomas, J. B.; Vetter, T. W.; Welch, M. J.; Wise, S. A.; Wood, L. J.; Guthrie, W. F.; Hagwood, C. R.; Leigh, S. D.; Yen, J. H.; Zhang, N.-F.; Chaudhary-Webb, M.; Chen, H.; Fazili, Z.; LaVoie, D. J.; McCoy, L. F.; Momin, S. S.; Paladugula, N.; Pendergrast, E. C.; Pfeiffer, C. M.; Powers, C. D.; Rabinowitz, D.; Rybak, M. E.; Schleicher, R. L.; Toombs, B. M. H.; Xu, M.; Zhang, M.; Castle, A. L. Anal. Chem. 2013, 85, 11732– 11738 DOI: 10.1021/ac402689t
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