多种代谢物调控蛋白质翻译后修饰的新机制研究和药物筛选策略  

Novel mechanisms of protein post-translational modifications regulated by multiple metabolites and strategies for drug screening

作　　者：杨思园 朱泽文 陈滢旭 杨丰瑞 吴鑫源 王江 李文洋 杨巍维 宋晓玉 陆晓杰 柳红 蒋维[2] 雷晓光[7] 赵世民 Siyuan Yang;Zewen Zhu;Yingxu Chen;Fengrui Yang;Xinyuan Wu;Jiang Wang;Wenyang Li;Weiwei Yang;Xiaoyu Song;Xiaojie Lu;Hong Liu;Wei Jiang;Xiaoguang Lei;Shimin Zhao(Shanghai Key Laboratory of Metabolic Remodeling and Health,Institute of Metabolism and Integrative Biology,Shanghai 200032,China;Key Laboratory of Metabolism and Molecular Medicine,Ministry of Education,Department of Biochemistry and Molecular Biology,School of Basic Medical Sciences,Shanghai Medical College,Fudan University,Shanghai 200032,China;Key Laboratory of Systems Health Science of Zhejiang Province,School of Life Science,Hangzhou Institute for Advanced Study,University of Chinese Academy of Sciences,Hangzhou 310024,China;Hefei National Research Center for Physical Sciences at the Microscale,University of Science and Technology of China,Hefei 230026,China;State Key Laboratory of Drug Research,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 201203,China;University of Chinese Academy of Sciences,Beijing 100049,China;Beijing National Laboratory for Molecular Sciences,Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education,College of Chemistry and Molecular Engineering,Peking University,Beijing 100871,China)

机构地区：[1]上海市代谢重塑与健康重点实验室,代谢与整合生物学研究院,上海200032 [2]复旦大学上海医学院基础医学院生物化学与分子生物学系代谢分子医学教育部重点实验室,上海200032 [3]浙江省系统健康科学重点实验室,国科大杭州高等研究院生命与健康科学学院,杭州310024 [4]中国科学技术大学合肥微尺度物质科学国家研究中心,合肥230026 [5]原创新药研究全国重点实验室,中国科学院上海药物研究所,上海201203 [6]中国科学院大学,北京100049 [7]北京分子科学国家研究中心,生物有机与分子工程教育部重点实验室,北京大学化学与分子工程学院,北京100871

出　　处：《中国科学:化学》2025年第4期986-996,共11页SCIENTIA SINICA Chimica

基　　金：国家自然科学基金(编号:91753207,92053203,92253305,91953108,92253305)资助项目。

摘　　要：代谢物是生物大分子修饰最主要的供体来源,环境或细胞内应激导致的代谢物改变信号也被整合到生命信号网络中.蛋白质磷酸化、乙酰化和甲基化等经典翻译后修饰(post-translational modification,PTM)以ATP、乙酰辅酶A和S-腺苷甲硫氨酸(SAM)等能量或物质表征代谢物为底物,传递共性代谢物信号;我们的研究发现,代谢物可以通过不同机制调控其作为供体外的其他PTM:巴豆酰辅酶A能作为酰基供体促进细胞周期依赖的EB1蛋白的巴豆酰化修饰,通过调控微管骨架的动态性维系基因组的稳定性;α-KIV和α-KG能够分别调控蛋白质磷酸化修饰和羟基化修饰,介导与自身代谢无关的TCR信号通路和Hedgehog信号通路;此外,天然植物的次生代谢物也能够促进AD相关蛋白的泛素化降解.这些发现为代谢物调控细胞生理病理的研究打开了新的角度和视野.基于代谢物调控翻译后修饰的新机制,我们以病理过程中的关键蛋白为例,高通量筛选了瞬时受体电位香草酸通道3蛋白(TRPV3)和菌源二肽基肽酶4(DPP4)的小分子抑制剂,为创新药的研发和疾病的干预提供了新的思路.Metabolites are the primary donors for the modification of biomacromolecules,and changes in metabolites caused by environmental or cellular stress signals are also integrated into life signal networks.Classical posttranslational modifications(PTMs),such as protein phosphorylation,acetylation,and methylation use energy or substance-indicating metabolites like ATP,acetyl-CoA,and S-adenosyl methionine(SAM)as substrates to convey common metabolic signals.Our research has found that metabolites can regulate other PTMs through different mechanisms outside of their role as donors:Crotonyl-CoA can act as an acyl donor to promote the crotonylation of cell cycle-dependent EB1 protein,maintaining genomic stability;α-KIV andα-KG can respectively regulate protein phosphorylation and hydroxylation modifications,mediating TCR signaling pathways and Hedgehog signaling pathway.In addition,natural metabolites can also promote the ubiquitination and degradation of AD-related proteins.Based on the new mechanisms of metabolite regulation of post-translational modifications,we have high-throughput screened small molecule inhibitors of the transient receptor potential vanilloid channel 3 protein(TRPV3)and dipeptidyl peptidase-4(DPP4),using key proteins in pathological processes as examples,providing new ideas for the development of innovative drugs and the intervention of diseases.

关 键 词：生物大分子 翻译后修饰 代谢物调控 细胞信号 干预 

分 类 号：Q51[生物学—生物化学]