《生命科学》 2018, 30(11): 1236-1243

苏氨酰-tRNA合成酶的功能及其在药物开发中的应用

陈　云1，2，周小龙1*，王恩多1，2，3*

(1 中国科学院生物化学与细胞生物学研究所，分子细胞科学卓越创新中心/分子生物学国家重点实验室，上海 200031；2 中国科学院大学，北京 100049；3 上海科技大学，上海 200031)

摘　要：摘　要：苏氨酰-tRNA 合成酶(ThrRS) 的经典功能是负责合成苏氨酰-tRNA (Thr-tRNAThr)，后者被延伸因子转运到核糖体上参与蛋白质合成。随着生命体的不断进化，ThrRS 不断获得蛋白质合成之外的新功能，统称为非经典功能，多与细胞存活和营养压力有关，对于真核生物细胞稳态至关重要。基于看家蛋白质的重要地位，ThrRS 基因突变会导致严重的功能异常，对生命体的正常生命活动造成严重的损伤；同时，ThrRS 也成为疾病治疗的有效靶点。关于ThrRS 抑制剂的研究也在不断进行，尽管广谱抑制剂疏螺旋体素(borrelidin) 抑制效果明显，但较大的细胞毒性导致其临床应用受到限制。开发新一代有效的低毒性抑制剂成为现阶段研究者们致力完成的目标。

The functions of threonyl-tRNA synthetase and its application in drug development

CHEN Yun1，2， ZHOU Xiao-Long1*， WANG En-Duo1，2，3*

(1 State Key Laboratory of Molecular Biology， CAS Center for Excellence in Molecular Cell Science， Shanghai Institute of Biochemistry and Cell Biology， Chinese Academy of Sciences， Shanghai 200031， China; 2 University of Chinese Academy of Sciences， Beijing 100049， China; 3 ShanghaiTech University， Shanghai 200031， China)

Abstract: Abstract: The canonical function of threonyl-tRNA synthetase (ThrRS) is ligating Thr to its cognate tRNA to produce Thr-tRNAThr， which would be subsequently involved into ribosome for protein translation. In the evolutionary process of organisms， ThrRS has acquired new functions， which are essential for cellular homeostatic and mainly related to cellular survival and nutritional stress responses. Because ThrRS is a housekeeping protein， abnormal physiological responses would happen to the ThrRS mutants， and their life activities would be severely disturbed. On the other hand， targeting ThrRS becomes an effective treatment method， and researches on ThrRS inhibitors are also ongoing. Despite the significant inhibition activity， the cytotoxicity of the best-known ThrRS inhibitor borrelidin to normal epithelial cell makes the biggest barrier to its clinical application. Developing an efficient substitute with less toxicity to borrelidin is getting more and more important.