Bifunctional aminoacyl-tRNA synthetase (EPRS1) (EPRS1)

The Prolyl-tRNA synthetase (ProRS) domain is a catalytic component of the human bifunctional glutamyl-prolyl-tRNA synthetase (EPRS1), an enzyme essential for protein biosynthesis that attaches proline to its cognate tRNA [1]. Beyond its housekeeping role in translation, EPRS1 is a key member of the gamma-interferon-activated inhibitor of translation (GAIT) complex, which regulates the expression of inflammatory genes [4]. The ProRS domain is a validated therapeutic target for fibrotic diseases and certain cancers, as its inhibition activates the amino acid starvation response (AAR) pathway, leading to the downregulation of Type I collagen and other pro-fibrotic factors [2]. Small molecule inhibitors such as halofuginone and the more selective bersipansent (DWN12088) bind to the ProRS catalytic site, effectively blocking proline charging [3]. This mechanism is being explored for treating idiopathic pulmonary fibrosis and systemic sclerosis, though potential side effects related to the inhibition of global protein synthesis remain a consideration for clinical development [2]. This target is also of interest in infectious diseases, particularly malaria, where parasite ProRS can be selectively inhibited [2]. Sources: [1] UniProt P07814; [2] Keller et al. (2012) Nature 483:218-221; [3] Daewoong Pharmaceutical (NCT03707418); [4] Arif et al. (2009) Mol Cell 35:164-180.

Other names

Glutamyl-prolyl-tRNA synthetaseProlyl-tRNA synthetase 1GluProRSPIG32QARSEPRSEPRS1

Competitive inhibition of the prolyl-tRNA synthetase catalytic domain, preventing the formation of prolyl-tRNA and subsequently triggering the amino acid starvation response (AAR) pathway [2].