Abstract
Aminoacyl‐tRNA synthetases (ARSs) are ubiquitously expressed enzymes responsible for charging tRNAs with their cognate amino acids, therefore essential for the first step in protein synthesis. Although the majority of protein synthesis happens in the cytosol, an additional translation apparatus is required to translate the 13 mitochondrial DNA‐encoded proteins important for oxidative phosphorylation. Most ARS genes in these cellular compartments are distinct, but two genes are common, encoding aminoacyl‐tRNA synthetases of glycine (GARS) and lysine (KARS) in both mitochondria and the cytosol. Mutations in the majority of the 37 nuclear‐encoded human ARS genes have been linked to a variety of recessive and dominant tissue‐specific disorders. Current data indicate that impaired enzyme function could explain the pathogenicity, however not all pathogenic ARSs mutations result in deficient catalytic function; thus, the consequences of mutations may arise from other molecular mechanisms. The peripheral nerves are frequently affected, as illustrated by the high number of mutations in cytosolic and bifunctional tRNA synthetases causing Charcot–Marie–Tooth disease (CMT). Here we provide insights on the pathomechanisms of CMT‐causing tRNA synthetases with specific focus on the two bifunctional tRNA synthetases (GARS, KARS).
Highlights
Aminoacyl-tRNA synthetases (ARSs) are ubiquitously expressed enzymes responsible for charging tRNAs with their cognate amino acids, essential for the first step in protein synthesis
There are two groups of ARS enzymes: the cytosolic ARS, which are responsible for supplying aminoacyl-tRNA conjugates for general protein translation; mitochondrial ARSs, which are imported into the mitochondrial matrix and charge amino acids to their mitochondrial genomeencoded tRNA molecules
All mt-ARSs are synthesised in the cytosol; addressed to, and imported into, the mitochondria due to the Abbreviations ARSAL, Autosomal Recessive Spastic Ataxia with Leukoencephalopathy; ARSs, Aminoacyl-tRNA synthetases; Charcot– Marie–Tooth disease (CMT), Charcot–Marie–Tooth disease; GARS, glycyl-ARS; MLASA, mitochondrial myopathy, lactic acidosis and sideroblastic anaemia; multitRNA synthetase complex (MSC), multi-tRNA synthetase complex; NMJs, neuromuscular junctions; VEGF, vascular endothelial growth factor
Summary
Aminoacyl-tRNA synthetases (ARSs) are ubiquitously expressed enzymes responsible for charging tRNAs with their cognate amino acids, essential for the first step in protein synthesis. Aminoacyl-tRNA synthetase proteins (ARS) are a family of nuclear-encoded enzymes that ensure correct translation of the genetic code by conjugating each of the 20 amino acids to their cognate tRNA molecule [1,2,3]. This aminoacylation reaction provides the substrate for the protein translation process. All mt-ARSs are synthesised in the cytosol; addressed to, and imported into, the mitochondria due to the Abbreviations ARSAL, Autosomal Recessive Spastic Ataxia with Leukoencephalopathy; ARSs, Aminoacyl-tRNA synthetases; CMT, Charcot–Marie–Tooth disease; GARS, glycyl-ARS; MLASA, mitochondrial myopathy, lactic acidosis and sideroblastic anaemia; MSC, multi-tRNA synthetase complex; NMJs, neuromuscular junctions; VEGF, vascular endothelial growth factor. No ARS2 mutations have been reported in human disease with an autosomal dominant mode of inheritance, all mutations are either homozygous or compound heterozygous (Fig. 1)
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