Glutamyl-prolyl-tRNA synthetase 1 (EPRS1) (EPRS1)

Glutamyl-prolyl-tRNA synthetase 1 (EPRS1), also frequently referred to as Prolyl-tRNA synthetase 1 (PARS1), is a bifunctional aminoacyl-tRNA synthetase that catalyzes the attachment of glutamic acid and proline to their respective tRNAs [1, 4]. In humans, it is a core component of the multi-tRNA synthetase complex (MSC) and plays a dual role in both protein translation and non-canonical signaling pathways, such as the GAIT (Gamma Interferon-Activated Inhibitor of Translation) complex, which regulates inflammatory gene expression [3, 8]. EPRS1 is a significant therapeutic target in fibrotic diseases, including idiopathic pulmonary fibrosis and cardiac fibrosis, because its inhibition selectively reduces the translation of proline-rich proteins like collagen [5, 12, 18]. It is also implicated in the progression of various cancers, such as multiple myeloma and T-cell acute lymphoblastic leukemia, where its high expression correlates with poor clinical outcomes [10, 15]. Pharmacological targeting of EPRS1, using inhibitors like halofuginone or the clinical-stage drug bersiporocin (DWN12088), works by blocking the prolyl-tRNA charging activity, thereby activating the amino acid response (AAR) pathway and inducing apoptosis in malignant cells [7, 19]. However, therapeutic development must balance efficacy with potential safety concerns, as complete loss of EPRS1 function has been linked to cardiac dysfunction and dilated cardiomyopathy in animal models [17].

Other names

Prolyl-tRNA synthetase 1PARS1ProRSBifunctional glutamate/proline--tRNA ligasePIG32Cell proliferation-inducing gene 32 proteinGlutamatyl-prolyl-tRNA synthetase

Inhibition of the prolyl-tRNA synthetase catalytic domain, either through proline-competitive or ATP-competitive binding, which leads to the accumulation of uncharged tRNA-Pro, activation of the GCN2-ATF4-mediated amino acid response (AAR) pathway, and the selective suppression of proline-rich protein synthesis, particularly type I collagen [5, 14, 19].