Medicinal Bioconvergence Research Center, Seoul National University, Yeongtong-gu, Suwon-si, Gyeonggi-do, Korea.
College of Pharmacy and Graduate School of Convergence Science and Technologies, Seoul National University, Yeongtong-gu, Suwon-si, Gyeonggi-do, Korea.
Nat Rev Drug Discov. 2019 Aug;18(8):629-650. doi: 10.1038/s41573-019-0026-3.
Aminoacyl-tRNA synthetases (ARSs) are essential enzymes for protein synthesis with evolutionarily conserved enzymatic mechanisms. Despite their similarity across organisms, scientists have been able to generate effective anti-infective agents based on the structural differences in the catalytic clefts of ARSs from pathogens and humans. However, recent genomic, proteomic and functionomic advances have unveiled unexpected disease-associated mutations and altered expression, secretion and interactions in human ARSs, revealing hidden biological functions beyond their catalytic roles in protein synthesis. These studies have also brought to light their potential as a rich and unexplored source for new therapeutic targets and agents through multiple avenues, including direct targeting of the catalytic sites, controlling disease-associated protein-protein interactions and developing novel biologics from the secreted ARS proteins or their parts. This Review addresses the emerging biology and therapeutic applications of human ARSs in diseases including autoimmune and rare diseases, and cancer.
氨酰-tRNA 合成酶（ARSs）是蛋白质合成所必需的酶，具有进化上保守的酶促机制。尽管它们在不同的生物体中具有相似性，但科学家们已经能够基于病原体和人类 ARS 催化裂缝的结构差异生成有效的抗感染药物。然而，最近的基因组、蛋白质组和功能组学的进展揭示了出人意料的与疾病相关的突变和人类 ARS 的表达、分泌和相互作用的改变，揭示了其在蛋白质合成中的催化作用之外的隐藏生物学功能。这些研究还通过多种途径揭示了它们作为新的治疗靶点和药物的丰富而未开发的来源的潜力，包括直接靶向催化位点、控制与疾病相关的蛋白质-蛋白质相互作用以及开发来自分泌的 ARS 蛋白或其部分的新型生物制剂。这篇综述探讨了人类 ARS 在包括自身免疫性疾病和罕见疾病以及癌症在内的疾病中的新兴生物学和治疗应用。
