Aminoacyl tRNASynthetases, Chemistry of

Abstract

Aminoacyl‐tRNA synthetases (aaRSs) compose a family of essential enzymes that attach amino acids covalently to tRNA molecules during protein synthesis. Some aaRSs possess a hydrolytic amino acid editing function to ensure the fidelity of protein synthesis. In addition, aminoacylation can occur by indirect pathways that rely on mischarged tRNA intermediates and enzymes other than aaRSs. Throughout evolution, structural and functional divergence of aaRSs has yielded diverse secondary roles. Likewise, aaRS‐like proteins with either sequence or structural similarities to synthetases exhibit functions that may or may not be related to aminoacylation. Many of these diverse aaRSs and aaRS‐like proteins have been capitalized on by the microbial world and by medical research as targets for therapeutic agents such as antibiotics.

Boron-containing inhibitors of synthetases

“…Class I RS's aminoacylate the 2 0 -hydroxyl group of the ribose ring of the terminal adenosine of tRNA whereas Class II RS's aminoacylate the 3 0 -hydroxyl group, with the exception of phenylalanine tRNA synthetase (PheRS). 53 Their central cellular function marks aminoacyl tRNA synthetases for therapeutic purposes and most activity in this area has revolved around inhibitors for anti-infective therapy, which has been reviewed. 54 To date, only one aminoacyl tRNA synthetase inhibitor, mupirocin, has been launched onto the market, although there are several promising candidates currently in clinical trials (Fig.…”

Structural Insights into the Polyphyletic Origins of Glycyl tRNA Synthetases

“…Bacterial GlyRS, however, belongs to the subclass IIc, together with PheRS, AlaRS, SepRS, and PylRS, the most heterogeneous group of the three subclasses ( 25 – 27 ). However, there are some studies that place AlaRS or bacterial GlyRS within subclass IIa and/or do not consider the existence of two types of GlyRS belonging to different subclasses ( 28 – 32 ).…”

Yeast Mitochondrial Leucyl-tRNA Synthetase CP1 Domain Has Functionally Diverged to Accommodate RNA Splicing at Expense of Hydrolytic Editing

“…The ϳ170-amino acid CP1 insertion splits the ATP binding Rossmann-fold that characterizes the aminoacylation active site of class I aminoacyl tRNA synthetases (16,19) and folds discretely into a separate domain. The CP1 domain is connected to the rest of the enzyme via two flexible ␤-strands (Fig.…”