tRNA synthetase: tRNA aminoacylation and beyond

Abstract

The aminoacyl-tRNA synthetases are prominently known for their classic function in the first step of protein synthesis, where they bear the responsibility of setting the genetic code. Each enzyme is exquisitely adapted to covalently link a single standard amino acid to its cognate set of tRNA isoacceptors. These ancient enzymes have evolved idiosyncratically to host alternate activities that go far beyond their aminoacylation role and impact a wide range of other metabolic pathways and cell signaling processes. The family of aminoacyl-tRNA synthetases have also been suggested as a remarkable scaffold to incorporate new domains that would drive evolution and the emergence of new organisms with more complex function. Because they are essential, the tRNA synthetases have served as pharmaceutical targets for drug and antibiotic development. The recent unfolding of novel important functions for this family of proteins offers new and promising pathways for therapeutic development to treat diverse human diseases.

The C/ebp-Atf response element (CARE) location reveals two distinct Atf4-dependent, elongation-mediated mechanisms for transcriptional induction of aminoacyl-tRNA synthetase genes in response to amino acid limitation

“…Further analysis will be required to determine if the genes for the mitochondrial enzymes respond to other cellular stresses. For the cytoplasmic enzymes, there appears to be no obvious correlation between the AA-responsive ARS genes and: (i) essential versus non-essential AA; (ii) Class 1 or Class 2 ARS protein structure; (iii) members of the multi-synthetase complex; or (iv) ARS proteins that are known to have additional, non-canonical activities (9,10,13). Related to gene specificity, there are additional questions raised by our results.…”

“…Global gene expression profiling, along with other functional studies, has demonstrated that Atf4-upregulated genes are involved in a broad spectrum of cellular functions and includes many members of AA tRNA synthetase (ARS) gene family (2,4–7). ARSs are a ubiquitously expressed and evolutionally conserved family of enzymes that link an AA to its cognate tRNA (8,9). This primary function of ARSs is highly conserved for all living organisms from bacteria to humans, but secondary functions of many ARSs are also quite common (9–13).…”

“…ARSs are a ubiquitously expressed and evolutionally conserved family of enzymes that link an AA to its cognate tRNA (8,9). This primary function of ARSs is highly conserved for all living organisms from bacteria to humans, but secondary functions of many ARSs are also quite common (9–13). These additional, non-canonical functions of ARSs, include involvement in translational and transcriptional regulation of gene expression, extra- and intra-cellular signaling, angiogenesis, inflammation and tumourigenesis.…”

Roles of aminoacyl-tRNA synthetases in immune regulation and immune diseases

“…Aminoacyl-tRNA synthetases (ARSs) are generally considered as "housekeepers" involved in protein synthesis, whose primary function is to catalyze the aminoacylation of transfer RNAs (tRNAs). This enzymatic reaction is conserved and proceeds mainly in two steps 1,2 . First, an amino acid and an adenosine triphosphate (ATP) molecule bind to the active site of the corresponding ARS to form an aminoacyl adenylate (amino acid-AMP) intermediate and simultaneously release a pyrophosphate (PPi).…”

Repairing tRNA termini: News from the 3' end

“…Specific features of tRNAs, called identity elements, allow aminoacyl-tRNA synthetases to distinguish the different amino acid-acceptor classes when charging tRNAs with their cognate amino acid. [4][5][6][7] In addition to the anticodon, structural information and nucleotide 73, the unpaired 3 0 -terminal position immediately before the CCA end, are often used as identity elements. The latter is therefore also called discriminator position/nucleotide/base.…”