Aminoacyl‐tRNA synthetases in medicine and disease

Peng Yao,Paul L Fox

doi:10.1002/emmm.201100626

Abstract

Aminoacyl-tRNA synthetases (ARSs) are essential and ubiquitous ‘house-keeping’ enzymes responsible for charging amino acids to their cognate tRNAs and providing the substrates for global protein synthesis. Recent studies have revealed a role of multiple ARSs in pathology, and their potential use as pharmacological targets and therapeutic reagents. The ongoing discovery of genetic mutations in human ARSs is increasing exponentially and can be considered an important determinant of disease etiology. Several chemical compounds target bacterial, fungal and human ARSs as antibiotics or disease-targeting medicines. Remarkably, ongoing exploration of noncanonical functions of ARSs has shown important contributions to control of angiogenesis, inflammation, tumourigenesis and other important physiopathological processes. Here, we summarize the roles of ARSs in human diseases and medicine, focusing on the most recent and exciting discoveries.

Highlights

Aminoacyl-tRNA synthetases (ARSs) are essential and ubiquitous ‘house-keeping’ enzymes responsible for charging amino acids to their cognate tRNAs and providingAminoacyl-tRNA synthetases (ARSs) comprise an ancient ubiquitous family of enzymes in all cells from three major kingdoms of life
The aminoacylation reaction is performed by a two-step noncanonical functions of ARSs has shown important contributions to control of angiogenesis, inflammation, tumourigenesis and other important physiopathological processes
The interaction between RagD and LARS is mediated by the non-catalytic C-termini of both proteins. Consistent with these findings, yeast LARS was identified as a sensor for TORC1 activation (Bonfils et al, 2012), suggesting evolutionary conservation of this important noncanonical function. It remains to be determined whether elevated LARS in cancer cells causes hyperactivation of mTOR complex 1 (mTORC1) signalling with pathological consequences such as tumourigenesis (Shin et al, 2008)

Summary

Introduction

Aminoacyl-tRNA synthetases (ARSs) are essential and ubiquitous ‘house-keeping’ enzymes responsible for charging amino acids to their cognate tRNAs and providing. All mitochondrial ARSs bearing genetic mutations causing human diseases exhibit compromised aminoacylation activity, and effects on noncanonical functions unrelated to translation have not been demonstrated. The etiology underlying human mitochondrial disorders might be restricted to defective enzymatic activities These observations raise an important question: Given that genetic mutations from mitochondrial ARSs affect fundamental mitochondrial functions, for example, translational repression of mitochondrial proteins and consequent respiratory chain defects, why do they cause a diversity of disease phenotypes in distinct affected tissues? Genetic mutations in either member of at least five cognate ARS-tRNA pairs (AARS2-mtT-DNAAla, EARS2-mtT-DNAGlu, HARS2-mtT-DNAHis, RARS2-mtT-DNAArg and YARS2-mtT-DNATyr) cause the same or similar pathological phenotypes, possibly due to a common loss-of-activity mechanism (Table 1). The high specificity of AN2690 for the fungal enzyme is possibly due to inefficient penetration of human cell plasma membranes or inaccessibility of LARS in the MSC

C Humans

Concluding remarks