Conservation and Diversification of tRNA t<sup>6</sup>A-Modifying Enzymes across the Three Domains of Life
The universal <i>N</i><sup>6</sup>-threonylcarbamoyladenosine (t<sup>6</sup>A) modification occurs at position 37 of tRNAs that decipher codons starting with adenosine. Mechanistically, t<sup>6</sup>A stabilizes structural configurations of the anticod...
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MDPI AG
2022-11-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/21/13600 |
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| author | Chenchen Su Mengqi Jin Wenhua Zhang |
| author_facet | Chenchen Su Mengqi Jin Wenhua Zhang |
| author_sort | Chenchen Su |
| collection | DOAJ |
| description | The universal <i>N</i><sup>6</sup>-threonylcarbamoyladenosine (t<sup>6</sup>A) modification occurs at position 37 of tRNAs that decipher codons starting with adenosine. Mechanistically, t<sup>6</sup>A stabilizes structural configurations of the anticodon stem loop, promotes anticodon–codon pairing and safeguards the translational fidelity. The biosynthesis of tRNA t<sup>6</sup>A is co-catalyzed by two universally conserved protein families of TsaC/Sua5 (COG0009) and TsaD/Kae1/Qri7 (COG0533). Enzymatically, TsaC/Sua5 protein utilizes the substrates of <i>L</i>-threonine, HCO<sub>3</sub><sup>−</sup>/CO<sub>2</sub> and ATP to synthesize an intermediate <i>L</i>-threonylcarbamoyladenylate, of which the threonylcarbamoyl-moiety is subsequently transferred onto the A37 of substrate tRNAs by the TsaD–TsaB –TsaE complex in bacteria or by the KEOPS complex in archaea and eukaryotic cytoplasm, whereas Qri7/OSGEPL1 protein functions on its own in mitochondria. Depletion of tRNA t<sup>6</sup>A interferes with protein homeostasis and gravely affects the life of unicellular organisms and the fitness of higher eukaryotes. Pathogenic mutations of YRDC, OSGEPL1 and KEOPS are implicated in a number of human mitochondrial and neurological diseases, including autosomal recessive Galloway–Mowat syndrome. The molecular mechanisms underscoring both the biosynthesis and cellular roles of tRNA t<sup>6</sup>A are presently not well elucidated. This review summarizes current mechanistic understandings of the catalysis, regulation and disease implications of tRNA t<sup>6</sup>A-biosynthetic machineries of three kingdoms of life, with a special focus on delineating the structure–function relationship from perspectives of conservation and diversity. |
| first_indexed | 2024-03-09T18:59:46Z |
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| language | English |
| last_indexed | 2024-03-09T18:59:46Z |
| publishDate | 2022-11-01 |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-955df9d38df641ce8b89ddc11022482a2023-11-24T05:10:38ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-11-0123211360010.3390/ijms232113600Conservation and Diversification of tRNA t<sup>6</sup>A-Modifying Enzymes across the Three Domains of LifeChenchen Su0Mengqi Jin1Wenhua Zhang2School of Life Sciences, Lanzhou University, 222 South Tianshui Road, Lanzhou 730030, ChinaSchool of Life Sciences, Lanzhou University, 222 South Tianshui Road, Lanzhou 730030, ChinaSchool of Life Sciences, Lanzhou University, 222 South Tianshui Road, Lanzhou 730030, ChinaThe universal <i>N</i><sup>6</sup>-threonylcarbamoyladenosine (t<sup>6</sup>A) modification occurs at position 37 of tRNAs that decipher codons starting with adenosine. Mechanistically, t<sup>6</sup>A stabilizes structural configurations of the anticodon stem loop, promotes anticodon–codon pairing and safeguards the translational fidelity. The biosynthesis of tRNA t<sup>6</sup>A is co-catalyzed by two universally conserved protein families of TsaC/Sua5 (COG0009) and TsaD/Kae1/Qri7 (COG0533). Enzymatically, TsaC/Sua5 protein utilizes the substrates of <i>L</i>-threonine, HCO<sub>3</sub><sup>−</sup>/CO<sub>2</sub> and ATP to synthesize an intermediate <i>L</i>-threonylcarbamoyladenylate, of which the threonylcarbamoyl-moiety is subsequently transferred onto the A37 of substrate tRNAs by the TsaD–TsaB –TsaE complex in bacteria or by the KEOPS complex in archaea and eukaryotic cytoplasm, whereas Qri7/OSGEPL1 protein functions on its own in mitochondria. Depletion of tRNA t<sup>6</sup>A interferes with protein homeostasis and gravely affects the life of unicellular organisms and the fitness of higher eukaryotes. Pathogenic mutations of YRDC, OSGEPL1 and KEOPS are implicated in a number of human mitochondrial and neurological diseases, including autosomal recessive Galloway–Mowat syndrome. The molecular mechanisms underscoring both the biosynthesis and cellular roles of tRNA t<sup>6</sup>A are presently not well elucidated. This review summarizes current mechanistic understandings of the catalysis, regulation and disease implications of tRNA t<sup>6</sup>A-biosynthetic machineries of three kingdoms of life, with a special focus on delineating the structure–function relationship from perspectives of conservation and diversity.https://www.mdpi.com/1422-0067/23/21/13600tRNA modification<i>N</i><sup>6</sup>-threonylcarbamoyladenosine synthetasesTsaC/Sua5TsaD/Kae1/Qri7KEOPSTsaD–TsaB–TsaE |
| spellingShingle | Chenchen Su Mengqi Jin Wenhua Zhang Conservation and Diversification of tRNA t<sup>6</sup>A-Modifying Enzymes across the Three Domains of Life International Journal of Molecular Sciences tRNA modification <i>N</i><sup>6</sup>-threonylcarbamoyladenosine synthetases TsaC/Sua5 TsaD/Kae1/Qri7 KEOPS TsaD–TsaB–TsaE |
| title | Conservation and Diversification of tRNA t<sup>6</sup>A-Modifying Enzymes across the Three Domains of Life |
| title_full | Conservation and Diversification of tRNA t<sup>6</sup>A-Modifying Enzymes across the Three Domains of Life |
| title_fullStr | Conservation and Diversification of tRNA t<sup>6</sup>A-Modifying Enzymes across the Three Domains of Life |
| title_full_unstemmed | Conservation and Diversification of tRNA t<sup>6</sup>A-Modifying Enzymes across the Three Domains of Life |
| title_short | Conservation and Diversification of tRNA t<sup>6</sup>A-Modifying Enzymes across the Three Domains of Life |
| title_sort | conservation and diversification of trna t sup 6 sup a modifying enzymes across the three domains of life |
| topic | tRNA modification <i>N</i><sup>6</sup>-threonylcarbamoyladenosine synthetases TsaC/Sua5 TsaD/Kae1/Qri7 KEOPS TsaD–TsaB–TsaE |
| url | https://www.mdpi.com/1422-0067/23/21/13600 |
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