Bifunctional glutamate--tRNA ligase (EPRS1) (EPRS1)

Human prolyl-tRNA synthetase (PRS) is a catalytic domain of the bifunctional enzyme glutamyl-prolyl-tRNA synthetase (EPRS1), which is responsible for the aminoacylation of tRNA with proline and glutamate (NIH Gene, 2026). It is a member of the class IIa aminoacyl-tRNA synthetase family and exists as part of the multi-tRNA synthetase complex (MSC) in the cytoplasm (AARS Online). Beyond its essential role in protein translation, EPRS1 performs non-canonical functions, including its participation in the GAIT complex to regulate inflammatory gene expression and its role as an effector in the mTOR-S6K1 pathway (Ovid, 2017). PRS is a validated therapeutic target for various conditions, including fibrotic diseases, autoimmune disorders, and certain cancers, due to its role in the synthesis of proline-rich proteins like collagen (AHA Journals, 2020). Inhibition of PRS activity by drugs such as halofuginone leads to the accumulation of uncharged tRNA-Pro, which activates the integrated stress response (ISR) via the GCN2 kinase (Nature, 2012). This activation results in the suppression of pro-inflammatory Th17 cell differentiation and the reduction of collagen production in myofibroblasts (PubMed, 2015). While PRS is essential for global protein synthesis, therapeutic windows are achieved by the heightened sensitivity of disease-associated proline-rich protein production to PRS inhibition (BioRxiv, 2021). Recent drug development efforts have focused on identifying selective small-molecule inhibitors that target the ATP or proline binding pockets of the PRS domain (MDPI, 2020).

Other names

Prolyl-tRNA synthetaseGlutamyl-prolyl-tRNA synthetasePRSEPRSPIG32Proline--tRNA ligaseCell proliferation-inducing gene 32 protein

Competitive inhibition of proline and ATP binding within the prolyl-tRNA synthetase domain, leading to the accumulation of uncharged tRNA-Pro and subsequent activation of the GCN2-mediated integrated stress response (ISR).