Publisher: Published by Blackwell Pub. on behalf of the Federation of European Biochemical Societies Country of Publication: England NLM ID: 101229646 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1742-4658 (Electronic) Linking ISSN: 1742464X NLM ISO Abbreviation: FEBS J Subsets: MEDLINE

Amino Acyl-tRNA Synthetases*/genetics , Amino Acyl-tRNA Synthetases*/metabolism , Amino Acyl-tRNA Synthetases*/antagonists & inhibitors , RNA, Transfer*/genetics , RNA, Transfer*/metabolism , Small Molecule Libraries*/therapeutic use , Small Molecule Libraries*/pharmacology, Humans ; Protein Biosynthesis/drug effects ; Protein Biosynthesis/genetics ; Mutation ; Animals

Aminoacyl-tRNA synthetases catalyze the ligation of a specific amino acid to its cognate tRNA. The resulting aminoacyl-tRNAs are indispensable intermediates in protein biosynthesis, facilitating the precise decoding of the genetic code. Pathogenic alleles in the aminoacyl-tRNA synthetases can lead to several dominant and recessive disorders. To date, disease-specific treatments for these conditions are largely unavailable. We review pathogenic human synthetase alleles, the molecular and cellular mechanisms of tRNA synthetase diseases, and emerging approaches to allele-specific treatments, including small molecules and nucleic acid-based therapeutics. Current treatment approaches to rescue defective or dysfunctional tRNA synthetase mutants include supplementation with cognate amino acids and delivery of cognate tRNAs to alleviate bottlenecks in translation. Complementary approaches use inhibitors to target the integrated stress response, which can be dysregulated in tRNA synthetase diseases.
(© 2024 The Author(s). The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)