Aminoacyl tRNA synthetases and their connections to disease

Abstract

Aminoacylation of transfer RNAs establishes the rules of the genetic code. The reactions are catalyzed by an ancient group of 20 enzymes (one for each amino acid) known as aminoacyl tRNA synthetases (AARSs). Surprisingly, the etiology of specific diseasesincluding cancer, neuronal pathologies, autoimmune disorders, and disrupted metabolic conditions-is connected to specific aminoacyl tRNA synthetases. These connections include heritable mutations in the genes for tRNA synthetases that are causally linked to disease, with both dominant and recessive disease-causing mutations being annotated. Because some disease-causing mutations do not affect aminoacylation activity or apparent enzyme stability, the mutations are believed to affect functions that are distinct from aminoacylation. Examples include enzymes that are secreted as procytokines that, after activation, operate in pathways connected to the immune system or angiogenesis. In addition, within cells, synthetases form multiprotein complexes with each other or with other regulatory factors and in that way control diverse signaling pathways. Although much has been uncovered in recent years, many novel functions, disease connections, and interpathway connections of tRNA synthetases have yet to be worked out.

Dual Role for Motif 1 Residues of Human Lysyl-tRNA Synthetase in Dimerization and Packaging into HIV-1

“…Aminoacyl-tRNA synthetases have been shown to function in a wide array of cellular processes that are distinct from aminoacylation and changes in oligomeric state, as well as posttranslational modifications have been shown to regulate these alternate functions (37)(38)(39)). An intriguing observation that highlights the dynamic nature of LysRS within the cell, is illustrated by its mobilization to the nucleus (37).…”

Screening of quinoline, 1,3-benzoxazine, and 1,3-oxazine-based small molecules against isolated methionyl-tRNA synthetase and A549 and HCT116 cancer cells including an in silico binding mode analysis

“…Methionine specifically is esterified to tRNA met by methionyltRNA synthetase (MRS), and elevated activity of MRS is reported in human cancers. [3][4][5] In cancer cells, targeting translational initiation is considered as one of the effective strategies to inhibit cell survival, proliferation and metastasis. 6 Selective inhibition of human MRS hence results in blockade of early events of protein synthesis, and thereby termination of global translation.…”

Dominant mutations in the tyrosyl-tRNA synthetase gene recapitulate in Drosophila features of human Charcot–Marie–Tooth neuropathy

“…Because many of the diseasecausing mutations in GlyRS do not affect the activity for aminoacylation or protein stability (9), and because GARS haploinsufficiency in the mouse does not lead to neuropathy (8), current speculation is that the neurodegenerative phenotype is caused by a gain of pathogenic function of mutant GlyRS, separable from aminoacylation. Indeed, expanded functions of tRNA synthetases in cell signaling pathways are now well known (10).…”