Glutamyl-prolyl tRNA synthetase (EPRS1) (EPRS1)

Glutamyl-prolyl tRNA synthetase (EPRS1) is a bifunctional aminoacyl-tRNA synthetase that plays a critical role in protein translation by charging tRNA with glutamate and proline (UniProt P07814). It is unique in higher eukaryotes for containing two distinct catalytic domains—GluRS and ProRS—connected by a linker region that facilitates its incorporation into the multi-tRNA synthetase complex (MSC) (PubMed: 22327440). Beyond translation, EPRS1 is a key component of the GAIT complex, which regulates the translation of specific mRNAs involved in the inflammatory response (PubMed: 17210612). The ProRS domain is a validated therapeutic target for fibrotic diseases, as its inhibition triggers the amino acid starvation response (AAR) and selectively reduces the production of proline-rich proteins like Type I and Type III collagen (PubMed: 22327440). Small molecule inhibitors such as halofuginone and the clinical candidate bersiprosylline (DWN12088) compete with proline for the active site of the ProRS domain, offering a strategy to treat idiopathic pulmonary fibrosis and potentially certain cancers where EPRS1 is overexpressed (PubMed: 33536250).

Other names

Bifunctional aminoacyl-tRNA synthetaseProlyl-tRNA synthetaseGlutamate-tRNA ligaseProline-tRNA ligaseEPRSPIG32GLNRSProlyl-tRNA synthetase domain of glutamyl-prolyl tRNA synthetase

Competitive inhibition of the prolyl-tRNA synthetase domain, preventing the charging of tRNA with proline, which triggers the amino acid starvation response and selectively inhibits the translation of proline-rich proteins like collagen.