Valine--tRNA ligase (VARS1) (VARS1)

Valine--tRNA ligase (VARS1) is a cytoplasmic enzyme belonging to the class I aminoacyl-tRNA synthetase family, responsible for the essential biological process of charging tRNA molecules with valine for protein synthesis. It catalyzes a two-step reaction involving the activation of valine with ATP to form a valyl-adenylate intermediate, followed by the transfer of the valyl moiety to the cognate tRNA(Val). Beyond its fundamental housekeeping role, VARS1 is critically involved in human pathology; biallelic recessive mutations in the VARS1 gene are associated with severe neurodevelopmental disorders characterized by microcephaly, intractable seizures, and cortical atrophy. In the context of oncology, VARS1 is frequently overexpressed and has been identified as a driver of tumor progression and therapy resistance in various cancers, including melanoma and prostate cancer, by facilitating codon-selective translational rewiring. Although no VARS1-targeted therapies are currently FDA-approved, the enzyme is an emerging therapeutic target, with research focusing on small-molecule inhibitors and dietary valine restriction as potential strategies to inhibit cancer growth and overcome drug resistance.

Other names

Valyl-tRNA synthetase 1Valyl-tRNA synthetaseValRSG7aSYVCValine--tRNA ligase 1, cytoplasmicValyl-tRNA synthetase 2

Catalyzes the attachment of valine to its cognate tRNA in a two-step reaction: first, valine is activated by ATP to form a valyl-adenylate (Val-AMP) intermediate; second, the valyl group is transferred to the 3'-terminal adenosine of tRNA(Val) to form valyl-tRNA(Val).