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...
| Main Authors: | , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-11-01
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| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/23/21/13600 |
| Summary: | 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. |
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| ISSN: | 1661-6596 1422-0067 |