蛋白质化学合成在蛋白质泛素化研究中的应用  

Application of chemical protein synthesis in the study of protein ubiquitination

作　　者：武世典 梁家伟 吴祥伟 邓智亨 刘磊[1] Shidian Wu;Jiawei Liang;Xiangwei Wu;Zhiheng Deng;Lei Liu(Ministry of Education Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology,Department of Chemistry,Tsinghua University,Beijing 100084,China)

机构地区：[1]清华大学化学系,生命有机磷化学及化学生物学教育部重点实验室,北京100084

出　　处：《中国科学:化学》2025年第4期825-846,共22页SCIENTIA SINICA Chimica

基　　金：国家自然科学基金(编号:22137005,92253302,22227810,T2488301)资助项目。

摘　　要：泛素化修饰调控真核细胞中绝大多数的生理与病理过程.在分子水平上深入解析蛋白质的泛素化过程能够提升人们对泛素化相关疾病的认知,促进新型诊疗策略的开发.蛋白质化学合成作为获取难以生物重组蛋白的策略,可获取各种定点泛素化修饰的蛋白体系,为泛素化机制的解析研究提供了重要方法基础.本文总结了蛋白质化学合成中所涉及的关键技术,包括多肽固相合成、蛋白片段连接以及蛋白折叠复性等.借助蛋白质化学合成,人们实现了泛素链、泛素化底物蛋白、泛素化学探针等研究工具的高效制备,并在此基础上阐明了一系列泛素化酶、去泛素化酶及靶向泛素系统的小分子药物的工作机制.蛋白质化学合成在泛素化研究中的广泛应用展示了化学生物学工具在推动人类健康与疾病研究、促进药物开发与精准治疗中的重要作用.Ubiquitination regulates almost all physiological and pathological processes in eukaryotes.Dissecting protein ubiquitination at the molecular level could promote the understanding of ubiquitin-related diseases and therefore facilitate the development of novel diagnostic and therapeutic strategies.Chemical protein synthesis provides powerful tools for obtaining proteins not accessible through recombinant expression,especially those site-specifically ubiquitinated proteins.In this review we summarize the pivotal technologies of chemical protein synthesis including SPPS,peptide segment ligation and protein refolding.With the help of chemical protein synthesis,tools like ubiquitin chains,ubiquitinated substrates and chemical probes could be efficiently prepared with high homogeneity and purity.On this basis,the working mechanism of a series of ubiquitination enzymes,deubiquitinases and small-molecule drugs has been resolved.The versatile application of chemical protein synthesis in dissecting ubiquitination mechanism demonstrates the tremendous potential of chemical biology tools in pushing forward the research of human health and disease,facilitating drug development and promoting precise therapeutic strategies.

关 键 词：翻译后修饰 泛素化 蛋白质化学合成 

分 类 号：Q51[生物学—生物化学]