基于N-磷酰化氨基酸探讨激酶磷转移机制  

Exploration of kinase phosphotransfer mechanism based on N-phosphoryl amino acids

作　　者：傅松森 李福来 黄碧玲 蔡华欢 倪锋 应见喜 刘艳[2] 付川[2] 高祥[3] 李艳梅[4] 赵玉芬 Songsen Fu;Fulai Li;Biling Huang;Huahuan Cai;Feng Ni;Jianxi Ying;Yan Liu;Chuan Fu;Xiang Gao;Yanmei Li;Yufen Zhao(Institute of Drug Discovery Technology,Ningbo University,Ningbo 315211,China;College of Chemistry and Chemical Engineering,Xiamen University,Xiamen 361005,China;School of Pharmaceutical Sciences,Xiamen University,Xiamen 361102,China;Department of Chemistry,Tsinghua University,Beijing 100084,China)

机构地区：[1]宁波大学新药技术研究院,宁波315211 [2]厦门大学化学化工学院,厦门361005 [3]厦门大学药学院,厦门361102 [4]清华大学化学系,北京100084

出　　处：《中国科学：化学》2023年第3期338-348,共11页SCIENTIA SINICA Chimica

基　　金：国家自然科学基金(编号:91856126,22107055,20972130,21778042,22274136,22237003,42003062,41876072);宁波市自然科学基金(编号:2021J131);宁波大学科研经费(编号:215-432000282);宁波市顶尖人才项目(编号:215-432094250)资助。

摘　　要：N-磷酰化的α-氨基酸可以发生多种磷转移反应,而且只有α-氨基酸可以被磷激活.在生命系统中,磷的转移在生物信息传递中扮演了关键角色.双组分系统(two-component system,TCS)是细菌感应并响应外界复杂环境最为重要的信号传导系统,其分子基础为磷酸根从ATP依次传递到组氨酸激酶的组氨酸(P–N键)和下游调控蛋白的天冬氨酸(P–OCO键);在高等生物中,ATP经激酶将磷酸根传递到底物蛋白的羟基(P–O键),催化中心中高度保守的酸性和碱性氨基酸不可或缺.如果N-磷酰化氨基酸是微型的TCS模型,那么高等生物激酶是否利用类似TCS的磷传递机制?本文总结了N-磷酰化α-氨基酸和激酶介导的磷转移过程,探讨N-磷酰化氨基酸模型作为磷转移系统“分子化石”的可能性,希望为激酶催化机制及基于激酶的新药研发提供新思路.Multiple phosphotransfer reactions can occur on N-phosphorylα-amino acids,and onlyα-amino acids can be activated by phosphorylation.In today’s living systems,the transfer of phosphorus still plays a dominant role in the information transmission.In prokaryotes,two-component system(TCS)is the most important signaling system for bacteria to sense and response the complex external environment.The molecular basis is that the phosphates delivered from histidine of histidine kinase(P–N bond)to aspartate of regulatory proteins(P–OCO bond).In higher organisms,γ-phosphate of ATP is transferred to the hydroxyl group of the substrate protein(P–O bond)via a kinase with highly conserved acidic and basic amino acids in its catalytic center.If N-phosphoryl amino acids are miniature models of TCS,do kinases of higher organisms utilize a phosphotransfer mechanism similar to TCS?This review summarizes the phosphotransfer processes mediated by N-phosphorylα-amino acids and kinases,discussing the possibility of the Nphosphoryl amino acid model as a“molecular fossil”of today’s phosphotransfer system,and hopes to provide new insights for the kinase catalytic mechanism and kinase development based on new drugs.

关 键 词：N-磷酰化氨基酸 激酶 磷转移 双组分系统 

分 类 号：TQ460.1[化学工程—制药化工] TQ426.97