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Synthesis and Structure Elucidation of Glutamyl-Queuosine
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Synthesis and Structure Elucidation of Glutamyl-Queuosine
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  • Alexander Pichler
    Alexander Pichler
    Department of Chemistry, Institute of Chemical Epigenetics, Ludwig-Maximilians-Universität München, Butenandtstr. 5-13, 81377 Munich, Germany
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  • Markus Hillmeier
    Markus Hillmeier
    Department of Chemistry, Institute of Chemical Epigenetics, Ludwig-Maximilians-Universität München, Butenandtstr. 5-13, 81377 Munich, Germany
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  • Matthias Heiss
    Matthias Heiss
    Department of Chemistry, Institute of Chemical Epigenetics, Ludwig-Maximilians-Universität München, Butenandtstr. 5-13, 81377 Munich, Germany
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    Orcidhttps://orcid.org/0000-0002-6770-9511
  • Elsa Peev
    Elsa Peev
    Department of Chemistry, Institute of Chemical Epigenetics, Ludwig-Maximilians-Universität München, Butenandtstr. 5-13, 81377 Munich, Germany
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  • Stylianos Xefteris
    Stylianos Xefteris
    Department of Chemistry, Institute of Chemical Epigenetics, Ludwig-Maximilians-Universität München, Butenandtstr. 5-13, 81377 Munich, Germany
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  • Barbara Steigenberger
    Barbara Steigenberger
    Mass Spectrometry Core Facility, Max Planck Institute of Biochemistry, Am Klopferspitz 18, Martinsried, 82152, Planegg, Germany
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  • Ines Thoma
    Ines Thoma
    Department of Chemistry, Institute of Chemical Epigenetics, Ludwig-Maximilians-Universität München, Butenandtstr. 5-13, 81377 Munich, Germany
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  • Markus Müller
    Markus Müller
    Department of Chemistry, Institute of Chemical Epigenetics, Ludwig-Maximilians-Universität München, Butenandtstr. 5-13, 81377 Munich, Germany
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    Orcidhttps://orcid.org/0000-0002-3579-3317
  • Marco Borsò
    Marco Borsò
    Department of Molecular Biology, Biomedical Center (BMC), Faculty of Medicine, Ludwig-Maximilians-Universität München, Großhaderner Str. 9, Martinsried, 82152 Planegg, Germany
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    Orcidhttps://orcid.org/0000-0001-7467-7960
  • Axel Imhof
    Axel Imhof
    Department of Molecular Biology, Biomedical Center (BMC), Faculty of Medicine, Ludwig-Maximilians-Universität München, Großhaderner Str. 9, Martinsried, 82152 Planegg, Germany
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    Orcidhttps://orcid.org/0000-0003-2993-8249
  • Thomas Carell*
    Thomas Carell
    Department of Chemistry, Institute of Chemical Epigenetics, Ludwig-Maximilians-Universität München, Butenandtstr. 5-13, 81377 Munich, Germany
    *Email: [email protected]
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    Orcidhttps://orcid.org/0000-0001-7898-2831
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Journal of the American Chemical Society

Cite this: J. Am. Chem. Soc. 2023, 145, 47, 25528–25532
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https://doi.org/10.1021/jacs.3c10075
Published November 15, 2023

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CC-BY-NC-ND 4.0 .

Abstract

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Queuosine is one of the most complex hypermodified RNA nucleosides found in the Wobble position of tRNAs. In addition to Queuosine itself, several further modified derivatives are known, where the cyclopentene ring structure is additionally modified by a galactosyl-, a mannosyl-, or a glutamyl-residue. While sugar-modified Queuosine derivatives are found in the tRNAs of vertebrates, glutamylated Queuosine (gluQ) is only known in bacteria. The exact structure of gluQ, particularly with respect to how and where the glutamyl side chain is connected to the Queuosine cyclopentene side chain, is unknown. Here we report the first synthesis of gluQ and, using UHPLC-MS-coinjection and NMR studies, we show that the isolated natural gluQ is the α-allyl-connected gluQ compound.

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In addition to the four canonical nucleosides Adenosine (A), Cytidine (C), Guanosine (G), and Uridine (U) RNA molecules, particularly tRNAs (tRNA), contain a large variety of modified noncanonical nucleosides (1) which influence their functions and properties. (2−4) Among these noncanonical nucleosides, Queuosine (Q, 1, Figure 1) is one of the most complex and highly modified. (5−7) It is found in cytosolic and mitochondrial tRNA of bacteria and eukaryotes and is located at position 34 in the anticodon loop, which is also called the “Wobble position”. (8) The Q-nucleoside is replacing G in GUN-anticodons and is therefore found in tRNATyr, tRNAAsp, tRNAHis, and tRNAAsn. (9,10)

Figure 1

Figure 1. Depiction of hypermodified nucleoside Q 1 and potential structure of glutamylated Q-derivatives.

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Queuosine 1 (Figure 1) is chemically derived from Guanosine (G). The main feature of the noncanonical base is the replacement of the N7 nitrogen atom by a C7 carbon, to which an unusual 1(S)-amino-2(R),3(S)-dihydroxycyclopent-4-ene unit is attached via a methylene linker. (7,11) The noncanonical nucleoside Q allows the tRNAs to decode synonymous codons by wobble base pairing. (12,13) In particular, it enables the decoding of both C and U nucleosides at the third position in the mRNA (mRNA) codon triplet during translation. In addition to altering decoding properties, Queuosine has also been reported to influence translational speed (14) and decoding fidelity. (15) In the absence of sufficient levels of the amino acid tyrosine, dietary supply of Queuine, which is the nucleobase of Queuosine, has been shown to be essential for survival in mice. (16,17)

In vertebrates further glycosylated derivatives of Queuosine are known, namely Galactosyl-Queuosine (galQ) and Mannosyl-Queuosine (manQ), whose structures were already elucidated. (5,18,19) In bacteria, a glutamylated version of Q (gluQ) was detected. (20,21) However, the function and exact structure of gluQ have not been fully elucidated. It is known that gluQ is an ester formed upon reaction of one of the free cyclopentene hydroxyl groups with l-glutamic acid 2. (20) It is, however, not known which carboxylic acid (α versus γ) is connected to which OH-group (allyl versus homoallyl, Figure 1).

To elucidate the structure, we performed a classical total synthesis approach of different gluQ derivatives and compared the compounds with natural gluQ isolated from E. coli RNA. The data allowed us to conclude that, in natural gluQ, the α-COOH of l-glutamic acid is connected to the allyl-OH group.

For the synthesis of the different gluQ derivatives, we first prepared 7-formyl-7-deazaguanosine nucleoside precursor 3 (Scheme 1). Reaction of formic acid methylester 4 with chloroacetonitrile and NaOMe afforded formyl chloroacetonitrile, which was coupled to 1,3-diamino-5-hydroxypyrimidine 5 in a Hantzsch pyrrole synthesis to generate preQ0 6. (22) In a two-step procedure, 6 was treated with Boc2O to afford the double N2-Boc- and O6-tert-butyl protected derivative 7. (23) A subsequent nucleosidation reaction was performed with an α-1-chloro-2,3,5-tri-O-benzylribose derivative 8, which was preformed from 2,3,5-tri-O-benzylribose 9 in an Appel chlorination reaction. After deprotonation of the heterocycle with NaH this reaction furnished the protected-preQ0 nucleoside 10 with good stereoselectivity (α/β = 1:4). Finally, the nitrile was reduced to the imine with DIBAL-H, which yielded the aldehyde 3 after hydrolysis. (24)

Scheme 1

Scheme 1. Synthesis of the Key Nucleoside Precursor 3 via Nucleosidation of α-1-Chloro-2,3,5-tri-O-benzylribofuranose 8 with Protected preQ07
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This key 7-formyl-7-deazaguanosine nucleoside 3 was subsequently subjected to a reductive amination with different glutamylated 1(S)-amino-2(R),3(S)-dihydroxycyclopent-4-enes (Schemes 2 and 3).

Scheme 2

Scheme 2. Synthesis of the Protected gluQ Derivatives, in Which the γ-COOH Group Is Connected to (a) the Homoallyl-OH Group and (b) the Allyl-OH Group; (c) Full Deprotection of the Allyl- and Homoallyl Connected Versions of gluQ
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Scheme 3

Scheme 3. Synthesis of the Protected gluQ Derivatives in Which the α-COOH Group Is Connected to (a) the Homoallyl-OH Group and (b) the Allyl-OH Group; (c) Full Deprotection of the Allyl- and Homoallyl Connected Versions of gluQ
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For the synthesis of the allyl- and homoallyl-gluQ derivatives, in which the glutamyl unit is connected via the γ-COOH group, we used the syntheses outlined in Scheme 2. Starting points were the 4-O-PMB and 5-O-SEM protected cyclopentene derivatives 11 and 12. The compounds 11 and 12 were prepared as recently reported by us. (18) To obtain the correct regioisomers 13 and 14 (Scheme 2a,b), we used the N-Boc and α-COOtBu protected l-glutamic acid 15 derivative for the EDC induced coupling. The subsequent Fmoc deprotection with NaN3 (25) to avoid basic conditions yielded the corresponding amino compounds 16 and 17, which were used in a reductive amination affording 18 and 19.

Subsequent deprotection with BCl3 furnished the γ-COOH coupled homoallyl and allyl gluQ derivatives 20 and 21 (Scheme 2c). However, under these harsh deprotection conditions, the majority of the compound hydrolyzed to Queuosine. Additionally, while the protected compounds (18 and 19) could be isolated in pure form, the HPL chromatogram of the deprotected compounds provided only a single, but identical peak for both 20 and 21. NMR analysis of the individual peaks showed, however, signals from two mixed molecular species. With the assistance of 2D-NMR, we could assign both possible regioisomers of the γ-COOH coupled gluQ in both samples (Figure 2). The preparation of pure regioisomers seemed difficult at this stage.

Figure 2

Figure 2. Zoom into the NMR-spectrum (D2O) of deprotected 18, yielding an allyl- and homoallyl-mixture of γ-gluQ derivatives connected via the γ-carboxylic acid. Isomeric ratio is determined by the integration of isolated signals. Full NMR spectra can be found in the Supporting Information.

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Before starting extensive attempts to separate the γ-connected homoallyl- and allyl-compounds 20 and 21, we decided to compare the mixture with the natural product to see if one of the compounds corresponds to the natural material. To this end, we harvested E. coli cells and isolated small RNAs using standard procedures. After breaking down the RNA to the nucleoside level, using enzymatic digestion at slightly acidic conditions, we performed UHPLC-MS-coinjection experiments with the mixture of 20 and 21. First, upon injection of only the E. coli isolated and digested RNA into the UHPLC-MS device, we could detect a signal at 15.37 min corresponding to natural gluQ (Figure 3a, b). When we next coinjected the mixture of the allyl/homoallyl γ-gluQ (20 and 21) and the digested RNA, we detected two clearly distinguishable signals at 15.32 and 15.61 min. These data show that neither of the two coeluting γ-gluQ compounds (Supp. Figure 1) is identical with the natural product (Figure 3c).

Figure 3

Figure 3. Results of the UHPLC-MS-coinjection experiments of γ-gluQ with natural gluQ obtained from E. coli RNA. (a) Digested RNA from E. coli only. (b) Mass spectra of the natural gluQ compound. *Co-eluting background signal. (c) Digested RNA from E. coli + γ-gluQ mixture 20 and 21.

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The synthesis of the allyl- and homoallyl-α-carboxylic ester derivatives was performed, as shown in Scheme 3a and b. For the α-connected homoallyl compound (Scheme 3a), we again started with the 4-O-PMB-protected cyclopentene unit 11. Esterification of a N-Boc and γ-COOtBu protected l-glutamate derivative 22 generated amino acid coupled cyclopentene 23. Subsequent removal of the Fmoc group under nonbasic conditions with NaN3 (25) gave the free amine 24, which was used to perform the reductive amination reaction with 3 to obtain the protected α-homoallyl-gluQ derivative 25. For the synthesis of the α-COOH esterified allyl-gluQ derivative (Scheme 3b), we again used the 5-O-SEM-protected cyclopentene 12. The subsequent esterification to 26, Fmoc-deprotection to 27, and reductive amination with 3 provided the protected α-allyl-gluQ derivative 28. We subsequently carefully deprotected both compounds using BCl3 at −90 °C, followed by mild neutralization of the reagent with MeOH. This ensured the integrity of the labile ester bond during deprotection, avoiding most of the degradation to Queuosine (Scheme 3c).

Again, both compounds proved to be indistinguishable from each other in the chromatographic analysis. Subsequent NMR analysis showed again the presence of a mixture of both α-allyl and α-homoallyl species. Coinjection with the natural material, however, showed a perfect overlap of the peaks, proving that one of the two α-regioisomers had to be the correct compound (Supp. Figure 2). We therefore tried to separate the two synthetic isomers first using CE-MS, this however without success (Supp. Figure 3). With the working hypothesis that a potential interconversion of the two isomers might be a very fast process in aqueous solutions, therefore making separation in the liquid phase extremely difficult, we attempted analysis in the gas phase by TIMS-TOF MS. Indeed, using this technique, we could detect two signals corresponding to the two gluQ isomers (Supp. Figure 4). Upon further development of the HPLC-MS method, however, we could finally achieve separation of the α-allyl-gluQ from the α-homoallyl-gluQ also in liquid phase.

With the adjusted HPLC conditions, we were then able to obtain the synthetic α-allyl- and α-homoallyl compounds 29 and 30 in pure form and assigned the structures using 13C/1H and 15N/1H HMBC spectra. Characteristic for the two compounds were the 3J-couplings between the bridging N atom and the tertiary homoallyl H atom and the 3J-coupling of this H atom to the C atom of the carboxyl group of the amino acid residue.

To our surprise, under the optimized deprotection conditions the deprotection of both the allyl compound 28 and the homoallyl compound 25 gave a mixture of allyl:homoallyl compounds in a ratio of about 25:3 as determined by HPLC (Supp. Figure 5). As expected, the amino acid side chain can obviously fluctuate between the two hydroxyl groups with a preference for the allyl-isomer under the given deprotection conditions. We noted, however, that both are rather unstable in water because they degrade quickly to Queuosine, potentially because of the neighboring hydroxyl group assisting the hydrolysis. The instability of gluQ has previously been reported. (26) We found, however, that the compounds can be stabilized in an aqueous solution at a pH range between pH = 3.5 and 4.0. Under these conditions, only little degradation to Q and very little isomerization between allyl and homoallyl remained observable.

In order to study which of the compounds corresponds to the natural material, we next repeated the coinjection experiment using the improved HPLC method. While we detected two separate signals when we coinjected the α-homoallyl-gluQ 30, only one amplified signal was detected with the α-allyl-gluQ compound 29 upon coinjection (Figure 4b). To exclude the possibility of gluQ isomerizing during purification from E. coli or digestion of the RNA we subjected α-homoallyl-gluQ to the purification and digestion procedures without observing any isomerization (Supp. Figure 6), proving that α-allyl-gluQ is indeed the correct structure of the natural material. In addition, the natural material was observed to isomerize to the α-homoallyl-gluQ after isolation, confirming an identical behavior to our synthetic gluQ standard (Supp. Figure 7).

Figure 4

Figure 4. Results of the UHPLC-MS-coinjection experiments of α-allyl-gluQ and α-homoallyl-gluQ with natural gluQ obtained from E. coli RNA. (a) Digested RNA from E. coli only. (b) Left: digested RNA from E. coli with α-homoallyl-gluQ, resulting in two distinct signals. Right: digested RNA from E. coli + α-allyl-gluQ resulting in one amplified signal.

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In summary, we present here the first total synthesis of natural gluQ. Our experiments show that the natural gluQ is the α-connected allyl species with the chemical structure 29. Interesting is the observation that the compound is very much prone to hydrolysis, even at neutral pH values. This is potentially catalyzed by the neighboring OH-group. We show furthermore that the gluQ compound can interconvert between the allyl and the homoallyl form under specific conditions. Given the fact that hydrolysis is the dominant process in a physiological environment and isomerization─based on our final results─is very slow, we can be confident that the allyl position is the favored substrate for the truncated aminoacyl tRNA synthetase responsible for the formation of gluQ. Why does nature use an unstable modified nucleoside in a position of the anticodon loop that is critical for decoding genetic information? We believe that our improved protocols and structural elucidation can provide the basis for studies of the conformational dynamics of this unusual nucleoside during translation.

Supporting Information

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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacs.3c10075.

  • Synthetic procedures, NMR-spectra, CE-MS and TIMS-TOF data, Isolation of RNA from E. coli, further sample preparation and LC-MS parameters are attached in the Supporting Information. (PDF)

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Author Information

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  • Corresponding Author
  • Authors
    • Alexander Pichler - Department of Chemistry, Institute of Chemical Epigenetics, Ludwig-Maximilians-Universität München, Butenandtstr. 5-13, 81377 Munich, Germany
    • Markus Hillmeier - Department of Chemistry, Institute of Chemical Epigenetics, Ludwig-Maximilians-Universität München, Butenandtstr. 5-13, 81377 Munich, Germany
    • Matthias Heiss - Department of Chemistry, Institute of Chemical Epigenetics, Ludwig-Maximilians-Universität München, Butenandtstr. 5-13, 81377 Munich, Germany;  Orcidhttps://orcid.org/0000-0002-6770-9511
    • Elsa Peev - Department of Chemistry, Institute of Chemical Epigenetics, Ludwig-Maximilians-Universität München, Butenandtstr. 5-13, 81377 Munich, Germany
    • Stylianos Xefteris - Department of Chemistry, Institute of Chemical Epigenetics, Ludwig-Maximilians-Universität München, Butenandtstr. 5-13, 81377 Munich, Germany
    • Barbara Steigenberger - Mass Spectrometry Core Facility, Max Planck Institute of Biochemistry, Am Klopferspitz 18, Martinsried, 82152, Planegg, Germany
    • Ines Thoma - Department of Chemistry, Institute of Chemical Epigenetics, Ludwig-Maximilians-Universität München, Butenandtstr. 5-13, 81377 Munich, Germany
    • Markus Müller - Department of Chemistry, Institute of Chemical Epigenetics, Ludwig-Maximilians-Universität München, Butenandtstr. 5-13, 81377 Munich, Germany;  Orcidhttps://orcid.org/0000-0002-3579-3317
    • Marco Borsò - Department of Molecular Biology, Biomedical Center (BMC), Faculty of Medicine, Ludwig-Maximilians-Universität München, Großhaderner Str. 9, Martinsried, 82152 Planegg, Germany;  Orcidhttps://orcid.org/0000-0001-7467-7960
    • Axel Imhof - Department of Molecular Biology, Biomedical Center (BMC), Faculty of Medicine, Ludwig-Maximilians-Universität München, Großhaderner Str. 9, Martinsried, 82152 Planegg, Germany;  Orcidhttps://orcid.org/0000-0003-2993-8249
  • Author Contributions

    A.P. and M.H. contributed equally.

  • Funding

    We thank the Volkswagen Foundation for funding this research (grant EvoRib). This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program under grant agreement No 741912 (EPiR). Further support was obtained by the DFG program CRC1309 (325871075), the DFG program CRC1064 (213249687), the DFG Normalverfahren “prebiotic chemistry of modified nucleosides” (326039064) and the European Union’s Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement No 861381 (Nature-ETN).

  • Notes
    The authors declare no competing financial interest.

Acknowledgments

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We thank Stefanie Kaiser for helpful discussions.

Abbreviations

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Q

Queuosine

manQ

Mannosyl-Queuosine

galQ

Galactosyl-Queuosine

gluQ

Glutamyl-Queuosine

CE-MS

Capillary Electrophoresis–Mass Spectrometry

TIMS-TOF

Trapped Ion Mobility Spectrometry Time of Flight

References

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    Thumbs, P.; Ensfelder, T. T.; Hillmeier, M.; Wagner, M.; Heiss, M.; Scheel, C.; Schön, A.; Müller, M.; Michalakis, S.; Kellner, S.; Carell, T. Synthesis of galactosyl-queuosine and distribution of hypermodified Q-nucleosides in mouse tissues. Angew. Chem., Int. Ed. 2020, 59 (30), 12352– 12356,  DOI: 10.1002/anie.202002295
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    5
    Synthesis of Galactosyl-Queuosine and Distribution of Hyper-modified Q-Nucleosides in Mouse Tissues
    Thumbs, Peter; Ensfelder, Timm T.; Hillmeier, Markus; Wagner, Mirko; Heiss, Matthias; Scheel, Constanze; Schoen, Alexander; Mueller, Markus; Michalakis, Stylianos; Kellner, Stefanie; Carell, Thomas
    Angewandte Chemie, International Edition (2020), 59 (30), 12352-12356CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    Queuosine (Q) is a hypermodified RNA nucleoside that is found in tRNAHis, tRNAAsn, tRNATyr, and tRNAAsp. It is located at the wobble position of the tRNA anticodon loop, where it can interact with U as well as C bases located at the resp. position of the corresponding mRNA codons. In tRNATyr and tRNAAsp of higher eukaryotes, including human, the Q base is for yet unknown reasons further modified by the addn. of a galactose and a mannose sugar, resp. The reason for this addnl. modification, and how the sugar modification is orchestrated with Q formation and insertion, is unknown. Here, we report a total synthesis of the hypermodified nucleoside galactosyl-queuosine (galQ). The availability of the compd. enabled us to study the abs. levels of the Q-family nucleosides in six different organs of newborn and adult mice, and also in human cytosolic tRNA. Our synthesis now paves the way to a more detailed anal. of the biol. function of the Q-nucleoside family.
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  6. 6
    Klepper, F.; Jahn, E. M.; Hickmann, V.; Carell, T. Synthesis of the transfer-RNA nucleoside queuosine by using a chiral allyl azide intermediate. Angew. Chem., Int. Ed. 2007, 46 (13), 2325– 2327,  DOI: 10.1002/anie.200604579
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    6
    Synthesis of the transfer-RNA nucleoside queuosine by using a chiral allyl azide intermediate
    Klepper, Florian; Jahn, Eva-Maria; Hickmann, Volker; Carell, Thomas
    Angewandte Chemie, International Edition (2007), 46 (13), 2325-2327CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    The synthesis of transfer-RNA nucleoside queuosine I via reductive amination of a formyl and amino-substituted pyrrolo[2,3-d]pyrimidine nucleoside with a chiral isopropylidene-protected 3-amino-4,5-dihydroxycyclopentene, is described. The chiral isopropylidene-protected 3-amino-4,5-dihydroxycyclopentene was prepd. via stereoselective redn., followed by Mitsunobu amination of an allylic alc. to give allylic cyclopentenyl azide. During Mitsunobu amination, [3.3] sigmatropic rearrangement can be suppressed at just 0°C.
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  7. 7
    Nishimura, S. Structure, Biosynthesis, and Function of Queuosine in Transfer RNA. Prog. Nucleic Acid Res. Mol. Biol. 1983, 28, 49– 73,  DOI: 10.1016/S0079-6603(08)60082-3
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    7
    Structure, biosynthesis, and function of queuosine in transfer RNA
    Nishimura, Susumu
    Progress in Nucleic Acid Research and Molecular Biology (1983), 28 (), 49-73CODEN: PNMBAF; ISSN:0079-6603.
    A review with 108 refs.
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  8. 8
    Salinas-Giegé, T.; Giegé, R.; Giegé, P. tRNA biology in mitochondria. Int. J. Mol. Sci. 2015, 16 (3), 4518– 4559,  DOI: 10.3390/ijms16034518
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    8
    tRNA biology in mitochondria
    Salinas-Giege, Thalia; Giege, Richard; Giege, Philippe
    International Journal of Molecular Sciences (2015), 16 (3), 4518-4559CODEN: IJMCFK; ISSN:1422-0067. (MDPI AG)
    Mitochondria are the powerhouses of eukaryotic cells. They are considered as semi-autonomous because they have retained genomes inherited from their prokaryotic ancestor and host fully functional gene expression machineries. These organelles have attracted considerable attention because they combine bacterial-like traits with novel features that evolved in the host cell. Among them, mitochondria use many specific pathways to obtain complete and functional sets of tRNAs as required for translation. In some instances, tRNA genes have been partially or entirely transferred to the nucleus and mitochondria require precise import systems to attain their pool of tRNAs. Still, tRNA genes have also often been maintained in mitochondria. Their genetic arrangement is more diverse than previously envisaged. The expression and maturation of mitochondrial tRNAs often use specific enzymes that evolved during eukaryote history. For instance many mitochondria use a eukaryote-specific RNase P enzyme devoid of RNA. The structure itself of mitochondrial encoded tRNAs is also very diverse, as e.g., in Metazoan, where tRNAs often show non canonical or truncated structures. As a result, the translational machinery in mitochondria evolved adapted strategies to accommodate the peculiarities of these tRNAs, in particular simplified identity rules for their aminoacylation. Here, we review the specific features of tRNA biol. in mitochondria from model species representing the major eukaryotic groups, with an emphasis on recent research on tRNA import, maturation and aminoacylation.
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  9. 9
    Harada, F.; Nishimura, S. Possible anticodon sequences of tRNAHis, tRNAAsn, and tRNAAsp from Escherichia coli. Universal presence of nucleoside O in the first position of the anticodons of these transfer ribonucleic acid. Biochemistry 1972, 11 (2), 301– 308,  DOI: 10.1021/bi00752a024
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    9
    Possible anticodon sequences of tRNAHis, tRNAAsn, and tRNAAsp from Escherichia coli. Universal presence of nucleoside O in the first position of the anticodons of these transfer ribonucleic acid
    Harada, Fumio; Nishimura, Susumu
    Biochemistry (1972), 11 (2), 301-8CODEN: BICHAW; ISSN:0006-2960.
    An unidentified nucleoside, Q, was isolated from E. coli tRNAHis1, tRNAAsn, and tRNAAsp1. The nucleotide sequences of oligonucleotides contg. Q, obtained by RNase T1 digestion of these three tRNAs, were detd. by conventional techniques. Q seemed to be located in the first position of the anticodons of all these tRNAs. Q was not found in other E. coli tRNAs. Thus, E. coli tRNAs which recognize U and C in the third position and A in the second position of code words always contained Q. Q had more affinity for U than for C in codon-anticodon base pairing, since among the trinucleotides corresponding to code words, those ending with U always caused most stimulation of the binding of tRNAs contg. Q to ribosomes.
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  10. 10
    Katze, J. R.; Basile, B.; McCloskey, J. A. Queuine, a modified base incorporated posttranscriptionally into eukaryotic transfer RNA: wide distribution in nature. Science 1982, 216 (4541), 55– 56,  DOI: 10.1126/science.7063869
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    10
    Queuine, a modified base incorporated posttranscriptionally into eukaryotic transfer RNA: wide distribution in nature
    Katze, Jon R.; Basile, Brenda; McCloskey, James A.
    Science (Washington, DC, United States) (1982), 216 (4541), 55-6CODEN: SCIEAS; ISSN:0036-8075.
    queuine (I) [72496-59-4], a modified base found in tRNA, appears to be a new dietary factor. Mice required I for the expression of I-contg. tRNA, but apparently do not synthesize it. Significant amts. of free I are present in common plant and animal food products.
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  11. 11
    Kasai, H.; Ohashi, Z.; Harada, F.; Nishimura, S.; Oppenheimer, N. J.; Crain, P. F.; Liehr, J. G.; von Minden, D. L.; McCloskey, J. A. Structure of the modified nucleoside Q isolated from Escherichia coli transfer ribonucleic acid. 7-(4,5-cis-Dihydroxy-1-cyclopenten-3-ylaminomethyl)-7-deazaguanosine. Biochemistry 1975, 14 (19), 4198– 4208,  DOI: 10.1021/bi00690a008
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    11
    Structure of the modified nucleoside Q isolated from Escherichia coli transfer ribonucleic acid. 7-(4,5-cis-Dihydroxy-1-cyclopenten-3-ylaminomethyl)-7-deazaguanosine
    Kasai, H.; Ohashi, Z.; Harada, F.; Nishimura, S.; Oppenheimer, N. J.; Crain, P. F.; Liehr, J. G.; Von Minden, D. L.; McCloskey, J. A.
    Biochemistry (1975), 14 (19), 4198-208CODEN: BICHAW; ISSN:0006-2960.
    The structure of the unknown modified nucleoside Q, which is present in the 1st position of the anticodons of E. coli tRNATyr, tRNAHis, tRNAAsn and tRNAAsp, is proposed as 7-(4,5-cis-dihydroxy-1-cyclopenten-3-ylaminomethyl)-7-deazaguanosine. The structure of Q was deduced by means of its uv absorption, mass spectrometry, PMR spectroscopy, and studies of its chem. reactivity. The structure of Q is unique since it is a deriv. of 7-deazaguanosine having cyclopentenediol in the side chain at the C-7 position. This is the 1st example of purine skeleton modification in a nucleoside from tRNA.
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  12. 12
    Meier, F.; Suter, B.; Grosjean, H.; Keith, G.; Kubli, E. Queuosine modification of the wobble base in tRNAHis influences ‘in vivo’ decoding properties. EMBO J. 1985, 4 (3), 823– 827,  DOI: 10.1002/j.1460-2075.1985.tb03704.x
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    12
    Queuosine modification of the wobble base in tRNAHis influences 'in vivo' decoding properties
    Meier F; Suter B; Grosjean H; Keith G; Kubli E
    The EMBO journal (1985), 4 (3), 823-7 ISSN:0261-4189.
    The 'in vivo' decoding properties of four tRNAHis isoacceptors, two from Drosophila melanogaster and two from brewer's yeast, were studied after their microinjection, along with turnip yellow mosaic virus (TYMV) coat protein mRNA, into Xenopus laevis oocytes. The two Drosophila isoacceptors are identical besides containing either a guanosine (G) or the hypermodified nucleoside queuosine (Q) in the wobble position. The brewer's yeast isoacceptors differ by four bases in the anticodon stem, and by one base in the amino acceptor stem. Our results show that, under competing 'in vivo' conditions, the Drosophila tRNAHis with the anticodon GUG clearly prefers the histidine codon CAC to the codon CAU, whereas little preference is observed for the tRNAHis with the anticodon QUG for the codon CAU, and no preference for either codon by the two yeast isoacceptors. Hence, it can be concluded that the presence of the Q-base clearly affects the choice of the codon. This is the first demonstration of an 'in vivo' codon preference by tRNA isoacceptors differing in the modification of the wobble base during the elongation step of protein synthesis. These results imply that one function of the Q-base is at the translational level.
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  13. 13
    Morris, R. C.; Brown, K. G.; Elliott, M. S. The effect of queuosine on tRNA structure and function. J. Biomol. Struct. Dyn. 1999, 16 (4), 757– 774,  DOI: 10.1080/07391102.1999.10508291
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    13
    The effect of queuosine on tRNA structure and function
    Morris, Rana C.; Brown, Kenneth G.; Elliott, Mark S.
    Journal of Biomolecular Structure & Dynamics (1999), 16 (4), 757-774CODEN: JBSDD6; ISSN:0739-1102. (Adenine Press)
    Computational modeling was performed to det. the potential function of the queuosine modification of tRNA found in wobble position 34 of tRNAasp, tRNAasn, tRNAhis, and tRNAtyr. Using the crystal structure of tRNAasp and a tRNA-tRNA-mRNA complex model, we show that the queuosine modification serves as a structurally restrictive base for tRNA anticodon loop flexibility. An extended intraresidue and intramol. hydrogen bonding network is established by queuosine. The quaternary amine of the 7-aminomethyl side chain hydrogen bonds with the base's carbonyl oxygen. This positions the dihydroxycyclopentenediol ring of queuosine in proper orientation for hydrogen bonding with the backbone of the neighboring uridine 33 residue. The interresidue assocn. stabilizes the formation of a cross-loop hydrogen bond between the uridine 33 base and the phosphoribosyl backbone of the cytosine at position 36. Addnl. interactions between RNAs in the translation complex were studied with regard to potential codon context and codon bias effects. Neither steric nor electrostatic interaction occurs between aminoacyl- and peptidyl-site tRNA anticodon loops that are modified with queuosine. However, there is a difference in the strength of anticodon/codon assocns. (codon bias) based on the presence or lack of queuosine in the wobble position of the tRNA. Unmodified (guanosine-contg.) tRNAasp forms a very stable assocn. with cytosine (GAC), but is much less stable in complex with a uridine-contg. codon (GAU). Queuosine-modified tRNAasp exhibits no bias for either of cognate codons GAC or GAU and demonstrates a lower binding energy similar to the wobble pairing of guanosine-contg. tRNA with a GAU codon. This is proposed to be due to the inflexibility of the queuosine-modified anticodon loop to accommodate proper positioning for optimal Watson-Crick type assocns. A preliminary survey of codon usage patterns in oncodevelopmental vs. housekeeping gene transcripts suggests a significant difference in bias for the queuosine-assocd. codons. Therefore, the queuosine modification may have the potential to influence cellular growth and differentiation by codon bias-based regulation of protein synthesis for discrete mRNA transcripts.
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  14. 14
    Tuorto, F.; Legrand, C.; Cirzi, C.; Federico, G.; Liebers, R.; Müller, M.; Ehrenhofer Murray, A. E.; Dittmar, G.; Gröne, H. J.; Lyko, F. Queuosine modified tRNAs confer nutritional control of protein translation. EMBO J. 2018, 37 (18), e99777,  DOI: 10.15252/embj.201899777
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    There is no corresponding record for this reference.
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    Zaborske, J. M.; Bauer DuMont, V. L.; Wallace, E. W. J.; Pan, T.; Aquadro, C. F.; Drummond, D. A. A Nutrient-Driven tRNA Modification Alters Translational Fidelity and Genome-wide Protein Coding across an Animal Genus. PLoS Biol. 2014, 12 (12), e1002015,  DOI: 10.1371/journal.pbio.1002015
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    15
    A nutrient-driven tRNA modification alters translational fidelity and genome-wide protein coding across an animal genus
    Zaborske, John M.; Bauer DuMont, Vanessa L.; Wallace, Edward W. J.; Pan, Tao; Aquadro, Charles F.; Drummond, D. Allan
    PLoS Biology (2014), 12 (12), e1002015/1-e1002015/13, 13 pp.CODEN: PBLIBG; ISSN:1545-7885. (Public Library of Science)
    Natural selection favors efficient expression of encoded proteins, but the causes, mechanisms, and fitness consequences of evolved coding changes remain an area of aggressive inquiry. We report a large-scale reversal in the relative translational accuracy of codons across 12 fly species in the Drosophila/Sophophora genus. Because the reversal involves pairs of codons that are read by the same genomically encoded tRNAs, we hypothesize, and show by direct measurement, that a tRNA anticodon modification from guanosine to queuosine has coevolved with these genomic changes. Queuosine modification is present in most organisms but its function remains unclear. Modification levels vary across developmental stages in D. melanogaster, and, consistent with a causal effect, genes maximally expressed at each stage display selection for codons that are most accurate given stage-specific queuosine modification levels. In a kinetic model, the known increased affinity of queuosine-modified tRNA for ribosomes increases the accuracy of cognate codons while reducing the accuracy of near-cognate codons. Levels of queuosine modification in D. melanogaster reflect bioavailability of the precursor queuine, which eukaryotes scavenge from the tRNAs of bacteria and absorb in the gut. These results reveal a strikingly direct mechanism by which recoding of entire genomes results from changes in utilization of a nutrient.
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  16. 16
    Marks, T.; Farkas, W. R. Effects of a diet deficient in tyrosine and queuine on germfree mice. Biochem. Biophys. Res. Commun. 1997, 230 (2), 233– 237,  DOI: 10.1006/bbrc.1996.5768
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    16
    Effects of a diet deficient in tyrosine and queuine on germ-free mice
    Marks, T.; Farkas, W. R.
    Biochemical and Biophysical Research Communications (1997), 230 (2), 233-237CODEN: BBRCA9; ISSN:0006-291X. (Academic)
    A chem.-defined diet consisting of amino acids (including tyrosine), vitamins, trace elements, glucose, etc., known to support growth and reprodn. through many generations when fed to germ-free mice has been in use for many yr in our lab. Classical nutritional studies showed that tyrosine was not a dietary requirement for higher mammals if an adequate amt. of phenylalanine was present. Therefore, it was unexpected that when tyrosine was removed from this diet, the germ-free mice developed ocular, neurol. and other abnormalities which resulted in 100% fatalities usually within two wk. Adding tyrosine back to the diet prevented the abnormalities from occurring. Conventional mice with a normal intestinal flora showed none of these symptoms when fed the same tyrosine-deficient diet. We added queuine to the tyrosine-deficient diet at a concn. of 0.1 μM. The germ-free mice that were fed the diet supplemented with queuine were asymptomatic and remained alive until the termination of the expts.
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  17. 17
    Rakovich, T.; Boland, C.; Bernstein, I.; Chikwana, V. M.; Iwata-Reuyl, D.; Kelly, V. P. Queuosine deficiency in eukaryotes compromises tyrosine production through increased tetrahydrobiopterin oxidation. J. Biol. Chem. 2011, 286 (22), 19354– 19363,  DOI: 10.1074/jbc.M111.219576
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    17
    Queuosine deficiency in eukaryotes compromises tyrosine production through increased tetrahydrobiopterin oxidation
    Rakovich, Tatsiana; Boland, Coilin; Bernstein, Ilana; Chikwana, Vimbai M.; Iwata-Reuyl, Dirk; Kelly, Vincent P.
    Journal of Biological Chemistry (2011), 286 (22), 19354-19363CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)
    Queuosine (I) is a modified pyrrolopyrimidine nucleoside found in the anticodon loop of tRNA acceptors for the amino acids, tyrosine, asparagine, aspartic acid, and histidine. Because it is exclusively synthesized by bacteria, higher eukaryotes must salvage I or its nucleobase queuine (II) from food and gut microflora. Previously, animals made deficient in II died within 18 days of withdrawing tyrosine, a nonessential amino acid, from the diet. Here, the authors show that human HepG2 cells deficient in II and mice made deficient in I-modified tRNA, by disruption of tRNA guanine transglycosylase, were compromised in their ability to produce tyrosine from phenylalanine. This has similarities to the disease, phenylketonuria, which arises from mutation in phenylalanine hydroxylase or from a decrease in the supply of its cofactor, tetrahydrobiopterin (BH4). Immunoblot and kinetic anal. of liver from tRNA guanine transglycosylase-deficient animals indicated normal expression and activity of phenylalanine hydroxylase. By contrast, BH4 levels were significantly decreased in the plasma, and both plasma and urine showed a clear elevation in dihydrobiopterin, an oxidn. product of BH4, despite normal activity of the salvage enzyme, dihydrofolate reductase. The data suggested that I modification limits BH4 oxidn. in vivo and thereby potentially impacts on numerous physiol. processes in eukaryotes.
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  18. 18
    Hillmeier, M.; Wagner, M.; Ensfelder, T. T.; Korytiakova, E.; Thumbs, P.; Müller, M.; Carell, T. Synthesis and structure elucidation of the human tRNA nucleoside mannosyl-queuosine. Nat. Commun. 2021, 12 (1), 7123,  DOI: 10.1038/s41467-021-27371-9
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    18
    Synthesis and structure elucidation of the human tRNA nucleoside mannosyl-queuosine
    Hillmeier, Markus; Wagner, Mirko; Ensfelder, Timm; Korytiakova, Eva; Thumbs, Peter; Mueller, Markus; Carell, Thomas
    Nature Communications (2021), 12 (1), 7123CODEN: NCAOBW; ISSN:2041-1723. (Nature Research)
    Abstr.: Queuosine (Q) is a structurally complex, non-canonical RNA nucleoside. It is present in many eukaryotic and bacterial species, where it is part of the anticodon loop of certain tRNAs. In higher vertebrates, including humans, two further modified queuosine-derivs. exist - galactosyl- (galQ) and mannosyl-queuosine (manQ). The function of these low abundant hypermodified RNA nucleosides remains unknown. While the structure of galQ was elucidated and confirmed by total synthesis, the reported structure of manQ still awaits confirmation. By combining total synthesis and LC-MS-co-injection expts., together with a metabolic feeding study of labeled hexoses, we show here that the natural compd. manQ isolated from mouse liver deviates from the literature-reported structure. Our data show that manQ features an α-allyl connectivity of its sugar moiety. The yet unidentified glycosylases that attach galactose and mannose to the Q-base therefore have a maximally different constitutional connectivity preference. Knowing the correct structure of manQ will now pave the way towards further elucidation of its biol. function.
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  19. 19
    Kasai, H.; Nakanishi, K.; Macfarlane, R. D.; Torgerson, D. F.; Ohashi, Z.; McCloskey, J. A.; Gross, H. J.; Nishimura, S. The structure of Q* nucleoside isolated from rabbit liver transfer ribonucleic acid. J. Am. Chem. Soc. 1976, 98 (16), 5044– 5046,  DOI: 10.1021/ja00432a071
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    19
    The structure of Q* nucleoside isolated from rabbit liver transfer ribonucleic acid
    Kasai, H.; Nakanishi, K.; Macfarlane, R. D.; Torgerson, D. F.; Ohashi, Z.; McCloskey, J. A.; Gross, H. J.; Nishimura, S.
    Journal of the American Chemical Society (1976), 98 (16), 5044-6CODEN: JACSAT; ISSN:0002-7863.
    The structures of the O*-nucleosides isolated from rabbit liver tRNA (1st position of the anticodon) were detd. as I and II by microspectral measurements. They are modified Q-nucleosides having mannose (major) and galactose (minor) units linked to position 4 of its cyclopentyl moiety and are the 1st modified tRNA nucleosides to carry sugars on the side-chain. Plasma desorption mass spectrometry was used for the 1st time to det. directly the mol. wt. without prior derivatization.
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  20. 20
    Blaise, M.; Becker, H. D.; Keith, G.; Cambillau, C.; Lapointe, J.; Giege, R.; Kern, D. A minimalist glutamyl-tRNA synthetase dedicated to aminoacylation of the tRNAAsp QUC anticodon. Nucleic Acids Res. 2004, 32 (9), 2768– 2775,  DOI: 10.1093/nar/gkh608
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    20
    A minimalist glutamyl-tRNA synthetase dedicated to aminoacylation of the tRNAAsp QUC anticodon
    Blaise, Mickael; Becker, Hubert Dominique; Keith, Gerard; Cambillau, Christian; Lapointe, Jacques; Giege, Richard; Kern, Daniel
    Nucleic Acids Research (2004), 32 (9), 2768-2775CODEN: NARHAD; ISSN:0305-1048. (Oxford University Press)
    Escherichia coli encodes YadB, a protein displaying 34% identity with the catalytic core of glutamyl-tRNA synthetase but lacking the anticodon-binding domain. We show that YadB is a tRNA modifying enzyme that evidently glutamylates the queuosine residue, a modified nucleoside at the wobble position of the tRNAAsp QUC anticodon. This conclusion is supported by a variety of biochem. data and by the inability of the enzyme to glutamylate tRNAAsp isolated from an E.coli tRNA-guanosine transglycosylase minus strain deprived of the capacity to exchange guanosine 34 with queuosine. Structural mimicry between the tRNAAsp anticodon stem and the tRNAGlu amino acid acceptor stem in prokaryotes encoding YadB proteins indicates that the function of these tRNA modifying enzymes, which we rename glutamyl-Q tRNAAsp synthetases, is conserved among prokaryotes.
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    Salazar, J.; Ambrogelly, A.; Crain, P.; McCloskey, J.; Söll, D. A truncated aminoacyl-tRNA synthetase modifies RNA. Nucleic Acids Res. 2004, 101 (20), 7536– 7541,  DOI: 10.1073/pnas.0401982101
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    Anthony, N. G.; Baiget, J.; Berretta, G.; Boyd, M.; Breen, D.; Edwards, J.; Gamble, C.; Gray, A. I.; Harvey, A. L.; Hatziieremia, S. Inhibitory Kappa B Kinase α (IKKα) Inhibitors That Recapitulate Their Selectivity in Cells against Isoform-Related Biomarkers. J. Med. Chem. 2017, 60 (16), 7043– 7066,  DOI: 10.1021/acs.jmedchem.7b00484
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    Inhibitory Kappa B Kinase α (IKKα) Inhibitors That Recapitulate Their Selectivity in Cells against Isoform-Related Biomarkers
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  1. Maxwell Sigal, Satomi Matsumoto, Adam Beattie, Takayuki Katoh, Hiroaki Suga. Engineering tRNAs for the Ribosomal Translation of Non-proteinogenic Monomers. Chemical Reviews 2024, 124 (10) , 6444-6500. https://doi.org/10.1021/acs.chemrev.3c00894
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  • Abstract

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    Figure 1

    Figure 1. Depiction of hypermodified nucleoside Q 1 and potential structure of glutamylated Q-derivatives.

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    Scheme 1

    Scheme 1. Synthesis of the Key Nucleoside Precursor 3 via Nucleosidation of α-1-Chloro-2,3,5-tri-O-benzylribofuranose 8 with Protected preQ07
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    Scheme 2

    Scheme 2. Synthesis of the Protected gluQ Derivatives, in Which the γ-COOH Group Is Connected to (a) the Homoallyl-OH Group and (b) the Allyl-OH Group; (c) Full Deprotection of the Allyl- and Homoallyl Connected Versions of gluQ
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    Scheme 3

    Scheme 3. Synthesis of the Protected gluQ Derivatives in Which the α-COOH Group Is Connected to (a) the Homoallyl-OH Group and (b) the Allyl-OH Group; (c) Full Deprotection of the Allyl- and Homoallyl Connected Versions of gluQ
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    Figure 2

    Figure 2. Zoom into the NMR-spectrum (D2O) of deprotected 18, yielding an allyl- and homoallyl-mixture of γ-gluQ derivatives connected via the γ-carboxylic acid. Isomeric ratio is determined by the integration of isolated signals. Full NMR spectra can be found in the Supporting Information.

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    Figure 3

    Figure 3. Results of the UHPLC-MS-coinjection experiments of γ-gluQ with natural gluQ obtained from E. coli RNA. (a) Digested RNA from E. coli only. (b) Mass spectra of the natural gluQ compound. *Co-eluting background signal. (c) Digested RNA from E. coli + γ-gluQ mixture 20 and 21.

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    Figure 4

    Figure 4. Results of the UHPLC-MS-coinjection experiments of α-allyl-gluQ and α-homoallyl-gluQ with natural gluQ obtained from E. coli RNA. (a) Digested RNA from E. coli only. (b) Left: digested RNA from E. coli with α-homoallyl-gluQ, resulting in two distinct signals. Right: digested RNA from E. coli + α-allyl-gluQ resulting in one amplified signal.

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  • References

    This article references 26 other publications.

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      Queuosine (Q) is a hypermodified RNA nucleoside that is found in tRNAHis, tRNAAsn, tRNATyr, and tRNAAsp. It is located at the wobble position of the tRNA anticodon loop, where it can interact with U as well as C bases located at the resp. position of the corresponding mRNA codons. In tRNATyr and tRNAAsp of higher eukaryotes, including human, the Q base is for yet unknown reasons further modified by the addn. of a galactose and a mannose sugar, resp. The reason for this addnl. modification, and how the sugar modification is orchestrated with Q formation and insertion, is unknown. Here, we report a total synthesis of the hypermodified nucleoside galactosyl-queuosine (galQ). The availability of the compd. enabled us to study the abs. levels of the Q-family nucleosides in six different organs of newborn and adult mice, and also in human cytosolic tRNA. Our synthesis now paves the way to a more detailed anal. of the biol. function of the Q-nucleoside family.
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      Mitochondria are the powerhouses of eukaryotic cells. They are considered as semi-autonomous because they have retained genomes inherited from their prokaryotic ancestor and host fully functional gene expression machineries. These organelles have attracted considerable attention because they combine bacterial-like traits with novel features that evolved in the host cell. Among them, mitochondria use many specific pathways to obtain complete and functional sets of tRNAs as required for translation. In some instances, tRNA genes have been partially or entirely transferred to the nucleus and mitochondria require precise import systems to attain their pool of tRNAs. Still, tRNA genes have also often been maintained in mitochondria. Their genetic arrangement is more diverse than previously envisaged. The expression and maturation of mitochondrial tRNAs often use specific enzymes that evolved during eukaryote history. For instance many mitochondria use a eukaryote-specific RNase P enzyme devoid of RNA. The structure itself of mitochondrial encoded tRNAs is also very diverse, as e.g., in Metazoan, where tRNAs often show non canonical or truncated structures. As a result, the translational machinery in mitochondria evolved adapted strategies to accommodate the peculiarities of these tRNAs, in particular simplified identity rules for their aminoacylation. Here, we review the specific features of tRNA biol. in mitochondria from model species representing the major eukaryotic groups, with an emphasis on recent research on tRNA import, maturation and aminoacylation.
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      Katze, Jon R.; Basile, Brenda; McCloskey, James A.
      Science (Washington, DC, United States) (1982), 216 (4541), 55-6CODEN: SCIEAS; ISSN:0036-8075.
      queuine (I) [72496-59-4], a modified base found in tRNA, appears to be a new dietary factor. Mice required I for the expression of I-contg. tRNA, but apparently do not synthesize it. Significant amts. of free I are present in common plant and animal food products.
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    11. 11
      Kasai, H.; Ohashi, Z.; Harada, F.; Nishimura, S.; Oppenheimer, N. J.; Crain, P. F.; Liehr, J. G.; von Minden, D. L.; McCloskey, J. A. Structure of the modified nucleoside Q isolated from Escherichia coli transfer ribonucleic acid. 7-(4,5-cis-Dihydroxy-1-cyclopenten-3-ylaminomethyl)-7-deazaguanosine. Biochemistry 1975, 14 (19), 4198– 4208,  DOI: 10.1021/bi00690a008
      11
      Structure of the modified nucleoside Q isolated from Escherichia coli transfer ribonucleic acid. 7-(4,5-cis-Dihydroxy-1-cyclopenten-3-ylaminomethyl)-7-deazaguanosine
      Kasai, H.; Ohashi, Z.; Harada, F.; Nishimura, S.; Oppenheimer, N. J.; Crain, P. F.; Liehr, J. G.; Von Minden, D. L.; McCloskey, J. A.
      Biochemistry (1975), 14 (19), 4198-208CODEN: BICHAW; ISSN:0006-2960.
      The structure of the unknown modified nucleoside Q, which is present in the 1st position of the anticodons of E. coli tRNATyr, tRNAHis, tRNAAsn and tRNAAsp, is proposed as 7-(4,5-cis-dihydroxy-1-cyclopenten-3-ylaminomethyl)-7-deazaguanosine. The structure of Q was deduced by means of its uv absorption, mass spectrometry, PMR spectroscopy, and studies of its chem. reactivity. The structure of Q is unique since it is a deriv. of 7-deazaguanosine having cyclopentenediol in the side chain at the C-7 position. This is the 1st example of purine skeleton modification in a nucleoside from tRNA.
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    12. 12
      Meier, F.; Suter, B.; Grosjean, H.; Keith, G.; Kubli, E. Queuosine modification of the wobble base in tRNAHis influences ‘in vivo’ decoding properties. EMBO J. 1985, 4 (3), 823– 827,  DOI: 10.1002/j.1460-2075.1985.tb03704.x
      12
      Queuosine modification of the wobble base in tRNAHis influences 'in vivo' decoding properties
      Meier F; Suter B; Grosjean H; Keith G; Kubli E
      The EMBO journal (1985), 4 (3), 823-7 ISSN:0261-4189.
      The 'in vivo' decoding properties of four tRNAHis isoacceptors, two from Drosophila melanogaster and two from brewer's yeast, were studied after their microinjection, along with turnip yellow mosaic virus (TYMV) coat protein mRNA, into Xenopus laevis oocytes. The two Drosophila isoacceptors are identical besides containing either a guanosine (G) or the hypermodified nucleoside queuosine (Q) in the wobble position. The brewer's yeast isoacceptors differ by four bases in the anticodon stem, and by one base in the amino acceptor stem. Our results show that, under competing 'in vivo' conditions, the Drosophila tRNAHis with the anticodon GUG clearly prefers the histidine codon CAC to the codon CAU, whereas little preference is observed for the tRNAHis with the anticodon QUG for the codon CAU, and no preference for either codon by the two yeast isoacceptors. Hence, it can be concluded that the presence of the Q-base clearly affects the choice of the codon. This is the first demonstration of an 'in vivo' codon preference by tRNA isoacceptors differing in the modification of the wobble base during the elongation step of protein synthesis. These results imply that one function of the Q-base is at the translational level.
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    13. 13
      Morris, R. C.; Brown, K. G.; Elliott, M. S. The effect of queuosine on tRNA structure and function. J. Biomol. Struct. Dyn. 1999, 16 (4), 757– 774,  DOI: 10.1080/07391102.1999.10508291
      13
      The effect of queuosine on tRNA structure and function
      Morris, Rana C.; Brown, Kenneth G.; Elliott, Mark S.
      Journal of Biomolecular Structure & Dynamics (1999), 16 (4), 757-774CODEN: JBSDD6; ISSN:0739-1102. (Adenine Press)
      Computational modeling was performed to det. the potential function of the queuosine modification of tRNA found in wobble position 34 of tRNAasp, tRNAasn, tRNAhis, and tRNAtyr. Using the crystal structure of tRNAasp and a tRNA-tRNA-mRNA complex model, we show that the queuosine modification serves as a structurally restrictive base for tRNA anticodon loop flexibility. An extended intraresidue and intramol. hydrogen bonding network is established by queuosine. The quaternary amine of the 7-aminomethyl side chain hydrogen bonds with the base's carbonyl oxygen. This positions the dihydroxycyclopentenediol ring of queuosine in proper orientation for hydrogen bonding with the backbone of the neighboring uridine 33 residue. The interresidue assocn. stabilizes the formation of a cross-loop hydrogen bond between the uridine 33 base and the phosphoribosyl backbone of the cytosine at position 36. Addnl. interactions between RNAs in the translation complex were studied with regard to potential codon context and codon bias effects. Neither steric nor electrostatic interaction occurs between aminoacyl- and peptidyl-site tRNA anticodon loops that are modified with queuosine. However, there is a difference in the strength of anticodon/codon assocns. (codon bias) based on the presence or lack of queuosine in the wobble position of the tRNA. Unmodified (guanosine-contg.) tRNAasp forms a very stable assocn. with cytosine (GAC), but is much less stable in complex with a uridine-contg. codon (GAU). Queuosine-modified tRNAasp exhibits no bias for either of cognate codons GAC or GAU and demonstrates a lower binding energy similar to the wobble pairing of guanosine-contg. tRNA with a GAU codon. This is proposed to be due to the inflexibility of the queuosine-modified anticodon loop to accommodate proper positioning for optimal Watson-Crick type assocns. A preliminary survey of codon usage patterns in oncodevelopmental vs. housekeeping gene transcripts suggests a significant difference in bias for the queuosine-assocd. codons. Therefore, the queuosine modification may have the potential to influence cellular growth and differentiation by codon bias-based regulation of protein synthesis for discrete mRNA transcripts.
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    14. 14
      Tuorto, F.; Legrand, C.; Cirzi, C.; Federico, G.; Liebers, R.; Müller, M.; Ehrenhofer Murray, A. E.; Dittmar, G.; Gröne, H. J.; Lyko, F. Queuosine modified tRNAs confer nutritional control of protein translation. EMBO J. 2018, 37 (18), e99777,  DOI: 10.15252/embj.201899777
      There is no corresponding record for this reference.
    15. 15
      Zaborske, J. M.; Bauer DuMont, V. L.; Wallace, E. W. J.; Pan, T.; Aquadro, C. F.; Drummond, D. A. A Nutrient-Driven tRNA Modification Alters Translational Fidelity and Genome-wide Protein Coding across an Animal Genus. PLoS Biol. 2014, 12 (12), e1002015,  DOI: 10.1371/journal.pbio.1002015
      15
      A nutrient-driven tRNA modification alters translational fidelity and genome-wide protein coding across an animal genus
      Zaborske, John M.; Bauer DuMont, Vanessa L.; Wallace, Edward W. J.; Pan, Tao; Aquadro, Charles F.; Drummond, D. Allan
      PLoS Biology (2014), 12 (12), e1002015/1-e1002015/13, 13 pp.CODEN: PBLIBG; ISSN:1545-7885. (Public Library of Science)
      Natural selection favors efficient expression of encoded proteins, but the causes, mechanisms, and fitness consequences of evolved coding changes remain an area of aggressive inquiry. We report a large-scale reversal in the relative translational accuracy of codons across 12 fly species in the Drosophila/Sophophora genus. Because the reversal involves pairs of codons that are read by the same genomically encoded tRNAs, we hypothesize, and show by direct measurement, that a tRNA anticodon modification from guanosine to queuosine has coevolved with these genomic changes. Queuosine modification is present in most organisms but its function remains unclear. Modification levels vary across developmental stages in D. melanogaster, and, consistent with a causal effect, genes maximally expressed at each stage display selection for codons that are most accurate given stage-specific queuosine modification levels. In a kinetic model, the known increased affinity of queuosine-modified tRNA for ribosomes increases the accuracy of cognate codons while reducing the accuracy of near-cognate codons. Levels of queuosine modification in D. melanogaster reflect bioavailability of the precursor queuine, which eukaryotes scavenge from the tRNAs of bacteria and absorb in the gut. These results reveal a strikingly direct mechanism by which recoding of entire genomes results from changes in utilization of a nutrient.
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    16. 16
      Marks, T.; Farkas, W. R. Effects of a diet deficient in tyrosine and queuine on germfree mice. Biochem. Biophys. Res. Commun. 1997, 230 (2), 233– 237,  DOI: 10.1006/bbrc.1996.5768
      16
      Effects of a diet deficient in tyrosine and queuine on germ-free mice
      Marks, T.; Farkas, W. R.
      Biochemical and Biophysical Research Communications (1997), 230 (2), 233-237CODEN: BBRCA9; ISSN:0006-291X. (Academic)
      A chem.-defined diet consisting of amino acids (including tyrosine), vitamins, trace elements, glucose, etc., known to support growth and reprodn. through many generations when fed to germ-free mice has been in use for many yr in our lab. Classical nutritional studies showed that tyrosine was not a dietary requirement for higher mammals if an adequate amt. of phenylalanine was present. Therefore, it was unexpected that when tyrosine was removed from this diet, the germ-free mice developed ocular, neurol. and other abnormalities which resulted in 100% fatalities usually within two wk. Adding tyrosine back to the diet prevented the abnormalities from occurring. Conventional mice with a normal intestinal flora showed none of these symptoms when fed the same tyrosine-deficient diet. We added queuine to the tyrosine-deficient diet at a concn. of 0.1 μM. The germ-free mice that were fed the diet supplemented with queuine were asymptomatic and remained alive until the termination of the expts.
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    17. 17
      Rakovich, T.; Boland, C.; Bernstein, I.; Chikwana, V. M.; Iwata-Reuyl, D.; Kelly, V. P. Queuosine deficiency in eukaryotes compromises tyrosine production through increased tetrahydrobiopterin oxidation. J. Biol. Chem. 2011, 286 (22), 19354– 19363,  DOI: 10.1074/jbc.M111.219576
      17
      Queuosine deficiency in eukaryotes compromises tyrosine production through increased tetrahydrobiopterin oxidation
      Rakovich, Tatsiana; Boland, Coilin; Bernstein, Ilana; Chikwana, Vimbai M.; Iwata-Reuyl, Dirk; Kelly, Vincent P.
      Journal of Biological Chemistry (2011), 286 (22), 19354-19363CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)
      Queuosine (I) is a modified pyrrolopyrimidine nucleoside found in the anticodon loop of tRNA acceptors for the amino acids, tyrosine, asparagine, aspartic acid, and histidine. Because it is exclusively synthesized by bacteria, higher eukaryotes must salvage I or its nucleobase queuine (II) from food and gut microflora. Previously, animals made deficient in II died within 18 days of withdrawing tyrosine, a nonessential amino acid, from the diet. Here, the authors show that human HepG2 cells deficient in II and mice made deficient in I-modified tRNA, by disruption of tRNA guanine transglycosylase, were compromised in their ability to produce tyrosine from phenylalanine. This has similarities to the disease, phenylketonuria, which arises from mutation in phenylalanine hydroxylase or from a decrease in the supply of its cofactor, tetrahydrobiopterin (BH4). Immunoblot and kinetic anal. of liver from tRNA guanine transglycosylase-deficient animals indicated normal expression and activity of phenylalanine hydroxylase. By contrast, BH4 levels were significantly decreased in the plasma, and both plasma and urine showed a clear elevation in dihydrobiopterin, an oxidn. product of BH4, despite normal activity of the salvage enzyme, dihydrofolate reductase. The data suggested that I modification limits BH4 oxidn. in vivo and thereby potentially impacts on numerous physiol. processes in eukaryotes.
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    18. 18
      Hillmeier, M.; Wagner, M.; Ensfelder, T. T.; Korytiakova, E.; Thumbs, P.; Müller, M.; Carell, T. Synthesis and structure elucidation of the human tRNA nucleoside mannosyl-queuosine. Nat. Commun. 2021, 12 (1), 7123,  DOI: 10.1038/s41467-021-27371-9
      18
      Synthesis and structure elucidation of the human tRNA nucleoside mannosyl-queuosine
      Hillmeier, Markus; Wagner, Mirko; Ensfelder, Timm; Korytiakova, Eva; Thumbs, Peter; Mueller, Markus; Carell, Thomas
      Nature Communications (2021), 12 (1), 7123CODEN: NCAOBW; ISSN:2041-1723. (Nature Research)
      Abstr.: Queuosine (Q) is a structurally complex, non-canonical RNA nucleoside. It is present in many eukaryotic and bacterial species, where it is part of the anticodon loop of certain tRNAs. In higher vertebrates, including humans, two further modified queuosine-derivs. exist - galactosyl- (galQ) and mannosyl-queuosine (manQ). The function of these low abundant hypermodified RNA nucleosides remains unknown. While the structure of galQ was elucidated and confirmed by total synthesis, the reported structure of manQ still awaits confirmation. By combining total synthesis and LC-MS-co-injection expts., together with a metabolic feeding study of labeled hexoses, we show here that the natural compd. manQ isolated from mouse liver deviates from the literature-reported structure. Our data show that manQ features an α-allyl connectivity of its sugar moiety. The yet unidentified glycosylases that attach galactose and mannose to the Q-base therefore have a maximally different constitutional connectivity preference. Knowing the correct structure of manQ will now pave the way towards further elucidation of its biol. function.
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    19. 19
      Kasai, H.; Nakanishi, K.; Macfarlane, R. D.; Torgerson, D. F.; Ohashi, Z.; McCloskey, J. A.; Gross, H. J.; Nishimura, S. The structure of Q* nucleoside isolated from rabbit liver transfer ribonucleic acid. J. Am. Chem. Soc. 1976, 98 (16), 5044– 5046,  DOI: 10.1021/ja00432a071
      19
      The structure of Q* nucleoside isolated from rabbit liver transfer ribonucleic acid
      Kasai, H.; Nakanishi, K.; Macfarlane, R. D.; Torgerson, D. F.; Ohashi, Z.; McCloskey, J. A.; Gross, H. J.; Nishimura, S.
      Journal of the American Chemical Society (1976), 98 (16), 5044-6CODEN: JACSAT; ISSN:0002-7863.
      The structures of the O*-nucleosides isolated from rabbit liver tRNA (1st position of the anticodon) were detd. as I and II by microspectral measurements. They are modified Q-nucleosides having mannose (major) and galactose (minor) units linked to position 4 of its cyclopentyl moiety and are the 1st modified tRNA nucleosides to carry sugars on the side-chain. Plasma desorption mass spectrometry was used for the 1st time to det. directly the mol. wt. without prior derivatization.
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    20. 20
      Blaise, M.; Becker, H. D.; Keith, G.; Cambillau, C.; Lapointe, J.; Giege, R.; Kern, D. A minimalist glutamyl-tRNA synthetase dedicated to aminoacylation of the tRNAAsp QUC anticodon. Nucleic Acids Res. 2004, 32 (9), 2768– 2775,  DOI: 10.1093/nar/gkh608
      20
      A minimalist glutamyl-tRNA synthetase dedicated to aminoacylation of the tRNAAsp QUC anticodon
      Blaise, Mickael; Becker, Hubert Dominique; Keith, Gerard; Cambillau, Christian; Lapointe, Jacques; Giege, Richard; Kern, Daniel
      Nucleic Acids Research (2004), 32 (9), 2768-2775CODEN: NARHAD; ISSN:0305-1048. (Oxford University Press)
      Escherichia coli encodes YadB, a protein displaying 34% identity with the catalytic core of glutamyl-tRNA synthetase but lacking the anticodon-binding domain. We show that YadB is a tRNA modifying enzyme that evidently glutamylates the queuosine residue, a modified nucleoside at the wobble position of the tRNAAsp QUC anticodon. This conclusion is supported by a variety of biochem. data and by the inability of the enzyme to glutamylate tRNAAsp isolated from an E.coli tRNA-guanosine transglycosylase minus strain deprived of the capacity to exchange guanosine 34 with queuosine. Structural mimicry between the tRNAAsp anticodon stem and the tRNAGlu amino acid acceptor stem in prokaryotes encoding YadB proteins indicates that the function of these tRNA modifying enzymes, which we rename glutamyl-Q tRNAAsp synthetases, is conserved among prokaryotes.
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    21. 21
      Salazar, J.; Ambrogelly, A.; Crain, P.; McCloskey, J.; Söll, D. A truncated aminoacyl-tRNA synthetase modifies RNA. Nucleic Acids Res. 2004, 101 (20), 7536– 7541,  DOI: 10.1073/pnas.0401982101
      There is no corresponding record for this reference.
    22. 22
      Anthony, N. G.; Baiget, J.; Berretta, G.; Boyd, M.; Breen, D.; Edwards, J.; Gamble, C.; Gray, A. I.; Harvey, A. L.; Hatziieremia, S. Inhibitory Kappa B Kinase α (IKKα) Inhibitors That Recapitulate Their Selectivity in Cells against Isoform-Related Biomarkers. J. Med. Chem. 2017, 60 (16), 7043– 7066,  DOI: 10.1021/acs.jmedchem.7b00484
      22
      Inhibitory Kappa B Kinase α (IKKα) Inhibitors That Recapitulate Their Selectivity in Cells against Isoform-Related Biomarkers
      Anthony, Nahoum G.; Baiget, Jessica; Berretta, Giacomo; Boyd, Marie; Breen, David; Edwards, Joanne; Gamble, Carly; Gray, Alexander I.; Harvey, Alan L.; Hatziieremia, Sophia; Ho, Ka Ho; Huggan, Judith K.; Lang, Stuart; Llona-Minguez, Sabin; Luo, Jia Lin; McIntosh, Kathryn; Paul, Andrew; Plevin, Robin J.; Robertson, Murray N.; Scott, Rebecca; Suckling, Colin J.; Sutcliffe, Oliver B.; Young, Louise C.; Mackay, Simon P.
      Journal of Medicinal Chemistry (2017), 60 (16), 7043-7066CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      IKKβ plays a central role in the canonical NF-kB pathway, which has been extensively characterized. The role of IKKα in the noncanonical NF-kB pathway, and indeed in the canonical pathway as a complex with IKKβ, is less well understood. One major reason for this is the absence of chem. tools designed as selective inhibitors for IKKα over IKKβ. Herein, we report for the first time a series of novel, potent, and selective inhibitors of IKKα. We demonstrate effective target engagement and selectivity with IKKα in U2OS cells through inhibition of IKKα-driven p100 phosphorylation in the noncanonical NF-kB pathway without affecting IKKβ-dependent IKappa-Bα loss in the canonical pathway. These compds. represent the first chem. tools that can be used to further characterize the role of IKKα in cellular signaling, to dissect this from IKKβ and to validate it in its own right as a target in inflammatory diseases.
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    23. 23
      Wang, R.-W.; Gold, B. A Facile Synthetic Approach to 7-Deazaguanine Nucleosides via a Boc Protection Strategy. Org. Lett. 2009, 11 (11), 2465– 2468,  DOI: 10.1021/ol9007537
      23
      A Facile Synthetic Approach to 7-Deazaguanine Nucleosides via a Boc Protection Strategy
      Wang, Ruo-Wen; Gold, Barry
      Organic Letters (2009), 11 (11), 2465-2468CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)
      An efficient route to the prepn. of 5-substituted 2-amino-7-((2R,4R,5R)-tetrahydro-4-hydroxy-5-(hydroxymethyl)furan-2-yl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one compds. has been developed by the condensation of ω-substituted aldehydes with 2,6-diaminopyrimidin-4(3H)-one, followed by Boc protection to afford the corresponding N2,N2,N7-tris-Boc-O4-t-Bu-5-substituted 2-amino-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one, which is amenable to direct condensation with 1-chloro-2-deoxy-3,5-di-O-p-toluoyl-α-D-erythro-pentofuranose. This route affords an efficient synthesis to 2-amino-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one, 2-amino-5-alkyl-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one, and guanine nucleosides.
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    24. 24
      Brooks, A. F.; Garcia, G. A.; Showalter, H. D. H. A short, concise synthesis of queuine. Tetrahedron Lett. 2010, 51 (32), 4163– 4165,  DOI: 10.1016/j.tetlet.2010.06.008
      24
      A short, concise synthesis of queuine
      Brooks, Allen F.; Garcia, George A.; Showalter, H. D. Hollis
      Tetrahedron Letters (2010), 51 (32), 4163-4165CODEN: TELEAY; ISSN:0040-4039. (Elsevier Ltd.)
      A short, concise synthesis of queuine (I) was accomplished in a 36% overall yield through a convergent scheme utilizing a reductive amination as the penultimate step. The synthesis demonstrates the utility of silylation to facilitate reactions of various pyrrolo[2,3-d]pyrimidine intermediates, and offers the possibility of easily accessing related pyrrolo[2,3-d]pyrimidines as well as making addnl. analogs of queuine.
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    25. 25
      Chen, C.-C.; Rajagopal, B.; Liu, X. Y.; Chen, K. L.; Tyan, Y.-C.; Lin, F.; Lin, P.-C. A mild removal of Fmoc group using sodium azide. Amino Acids 2014, 46 (2), 367– 374,  DOI: 10.1007/s00726-013-1625-7
      25
      A mild removal of Fmoc group using sodium azide
      Chen, Chun-Chi; Rajagopal, Basker; Liu, Xuan Yu; Chen, Kuan Lin; Tyan, Yu-Chang; Lin, Fu I.; Lin, Po-Chiao
      Amino Acids (2014), 46 (2), 367-374CODEN: AACIE6; ISSN:0939-4451. (Springer-Verlag GmbH)
      A mild method for effectively removing a fluorenylmethoxycarbonyl (Fmoc) group was developed and the synthesis of the target compds. was achieved using sodium azide (NaN3) as a suitable reagent. Without base, sodium azide completely deprotected Nα-Fmoc-amino acids in hours. The solvent-dependent conditions were carefully studied and then optimized by screening different sodium azide amts. and reaction temps. A variety of Fmoc-protected amino acids contg. residues masked with different protecting groups were efficiently and selectively deprotected by the optimized reaction. Finally, a biol. significant hexapeptide, angiotensin IV, was successfully synthesized by solid phase peptide synthesis using the developed sodium azide method for all Fmoc removals. The base-free condition provides a complement method for Fmoc deprotection in peptide chem. and modern org. synthesis. The title compds. thus formed included 5-L-isoleucine-3-8-angiotensin II (human angiotensin IV) and L-valyl-L-lysyl-L-α-aspartylglycyl-L-tyrosyl-L-isoleucine (scorpion toxin II).
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    26. 26
      Dubois, D. Y.; Blaise, M.; Becker, H. D.; Campanacci, V.; Keith, G.; Giege, R.; Cambillau, C.; Lapointe, J.; Kern, D. An aminoacyl-tRNA synthetase-like protein encoded by the Escherichia coli yadB gene glutamylates specifically tRNAAsp. Proc. Natl. Acad. Sci. U. S. A. 2004, 101 (20), 7530– 7535,  DOI: 10.1073/pnas.0401634101
      26
      An aminoacyl-tRNA synthetase-like protein encoded by the Escherichia coli yadB gene glutamylates specifically tRNAAsp
      Dubois, Daniel Y.; Blaise, Mickael; Becker, Hubert D.; Campanacci, Valerie; Keith, Gerard; Giege, Richard; Cambillau, Christian; Lapointe, Jacques; Kern, Daniel
      Proceedings of the National Academy of Sciences of the United States of America (2004), 101 (20), 7530-7535CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
      The product of the Escherichia coli yadB gene is homologous to the N-terminal part of bacterial glutamyl-tRNA synthetases (GluRSs), including the Rossmann fold with the acceptor-binding domain and the stem-contact fold. This GluRS-like protein, which lacks the anticodon-binding domain, does not use tRNAGlu as substrate in vitro nor in vivo, but aminoacylates tRNAAsp with glutamate. The yadB gene is expressed in wild-type E. coli as an operon with the dksA gene, which encodes a protein involved in the general stress response by means of its action at the translational level. The fate of the glutamylated tRNAAsp is not known, but its incapacity to bind elongation factor Tu suggests that it is not involved in ribosomal protein synthesis. Genes homologous to yadB are present only in bacteria, mostly in Proteobacteria. Sequence alignments and phylogenetic analyses show that the YadB proteins form a distinct monophyletic group related to the bacterial and organellar GluRSs (α-type GlxRSs superfamily) with ubiquitous function as suggested by the similar functional properties of the YadB homolog from Neisseria meningitidis.
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  • Supporting Information

    Supporting Information

    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacs.3c10075.

    • Synthetic procedures, NMR-spectra, CE-MS and TIMS-TOF data, Isolation of RNA from E. coli, further sample preparation and LC-MS parameters are attached in the Supporting Information. (PDF)


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