Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
, 5 (3), 332-43

Aminoacyl-tRNA Synthetases in Medicine and Disease


Aminoacyl-tRNA Synthetases in Medicine and Disease

Peng Yao et al. EMBO Mol Med.


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.


Figure 1
Figure 1. Genetic mutations in human cytosolic ARSs cause CMT disease
The domain organization and sites of genetic mutations in human KARS, AARS, YARS and GARS are shown.
Figure 2
Figure 2. Potential mechanisms underlying CMT caused by ARS mutations
Possible etiologic mechanisms of CMT are shown. (a) Defective aminoacylation activity; (b) defective editing activity; (c) destabilization or degradation; (d) aggregate formation; (e) defective dimerization; (f) abnormal nuclear import; (g) abnormal mitochondrial import; (h) abnormal localization in cytosolic granules; (i) gain-of-function by generation of new protein interactions; (j) loss of noncanonical function and (k) defective axonal transport. Genetic mutations in ARSs are indicated (red stars).
Figure 3
Figure 3. ARSs as drug targets

The anti-bacterial reagent mupirocin targets the bacterial IARS synthetic active site by blocking Ile-AMP binding.

The anti-fungal reagent AN2690 targets the yeast LARS editing active site by boron-mediated trapping of tRNALeu.

The anti-fibrotic reagent halofuginone targets synthetic active site of PRS in human EPRS, triggering the AAR pathway and inhibiting Th17-cell differentiation.

Figure 4
Figure 4. Noncanonical functions of ARSs in regulating cell functions
Recent discoveries of noncanonical functions of human ARSs and their underlying mechanisms. IFN-γ-induced release of EPRS from the MSC and assembly of the GAIT complex that mediates translational silencing of inflammation-related mRNAs. UV-triggered phosphorylation of MARS inhibits global translation and activates tumour suppressor MSC p18. SARS directs transcriptional repression of VEGFA during vertebrate vascular development. WARS mediates crosstalk between IFN-γ and p53 signalling pathway to activate p53. LARS acts as a leucine sensor in mTORC1 signalling to regulate cell size and autophagy. Laminin-stimulated membrane localization of KARS promotes cell migration. Human macrophages secret GARS to suppress tumour growth. See details in the text.

Similar articles

See all similar articles

Cited by 98 PubMed Central articles

See all "Cited by" articles


    1. Achilli F, Bros-Facer V, Williams HP, Banks GT, AlQatari M, Chia R, Tucci V, Groves M, Nickols CD, Seburn KL, et al. An ENU-induced mutation in mouse glycyl-tRNA synthetase (GARS) causes peripheral sensory and motor phenotypes creating a model of Charcot–Marie–Tooth type 2D peripheral neuropathy. Dis Model Mech. 2009;2:359–373. - PMC - PubMed
    1. Antonellis A, Ellsworth RE, Sambuughin N, Puls I, Abel A, Lee-Lin SQ, Jordanova A, Kremensky I, Christodoulou K, Middleton LT, et al. Glycyl tRNA synthetase mutations in Charcot–Marie–Tooth disease type 2D and distal spinal muscular atrophy type V. Am J Hum Genet. 2003;72:1293–1299. - PMC - PubMed
    1. Antonellis A, Green ED. The role of aminoacyl-tRNA synthetases in genetic diseases. Annu Rev Genomics Hum Genet. 2008;9:87–107. - PubMed
    1. Arif A, Jia J, Mukhopadhyay R, Willard B, Kinter M, Fox PL. Two-site phosphorylation of EPRS coordinates multimodal regulation of noncanonical translational control activity. Mol Cell. 2009;35:164–180. - PMC - PubMed
    1. Baker SJ, Zhang YK, Akama T, Lau A, Zhou H, Hernandez V, Mao W, Alley MR, Sanders V, Plattner JJ. Discovery of a new boron-containing antifungal agent, 5-fluoro-1,3-dihydro-1-hydroxy-2,1- benzoxaborole (AN2690), for the potential treatment of onychomycosis. J Med Chem. 2006;49:4447–4450. - PubMed

Publication types

MeSH terms