The structure of 4-hydroxylphenylpyruvate dioxygenase complexed with 4-hydroxylphenylpyruvic acid reveals an unexpected inhibition mechanism  

作　　者：Xiaoning Wang Hongyan Lin Junjun Liu Xinyun Zhao Xi Chen Wenchao Yang Guangfu Yang Chang-guo Zhan 

机构地区：[1]College of Chemistry and Material Science,South-Central University for Nationalities,Wuhan 430074,China [2]Key Laboratory of Pesticide&Chemical Biology of Ministry of Education,College of Chemistry,Central China Normal University,Wuhan 430079,China [3]School of Pharmacy,Tongji Medical College of Huazhong University of Science&Technology,Wuhan 430030,China [4]Department of Pharmaceutical Sciences,College of Pharmacy,University of Kentucky,Lexington,KY 40536,United States

出　　处：《Chinese Chemical Letters》2021年第6期1920-1924,共5页中国化学快报（英文版）

基　　金：supported by the National Key R&D Program(No.2018YFD0200100);National Natural Science Foundation of China(Nos.21837001,21273089,22007035,U20A2038);the Open Project Fund of the Key Laboratory of the Pesticides and Chemical Biology of Central China Normal University(No.2018-A01);the Fundamental Research Funds for the South-Central University for Nationalities(No.CZW20020);the Fundamental Research Funds for the Central Universities(No.KJ02072020-0657);Hubei Province Natural Science Foundation(No.2020CFB487)。

摘　　要：4-Hydroxyphenylpyruvate dioxygenase(HPPD)is an important target for both drug and pesticide discovery.As a typical Fe(II)-dependent dioxygenase,HPPD catalyzes the complicated transformation of 4-hydroxyphenylpyruvic acid(HPPA)to homogentisic acid(HGA).The binding mode of HPPA in the catalytic pocket of HPPD is a focus of research interests.Recently,we reported the crystal structure of Arabidopsis thaliana HPPD(At HPPD)complexed with HPPA and a cobalt ion,which was supposed to mimic the pre-reactive structure of At HPPD-HPPA-Fe(II).Unexpectedly,the present study shows that the restored At HPPD-HPPA-Fe(II)complex is still nonreactive toward the bound dioxygen.QM/MM and QM calculations reveal that the HPPA resists the electrophilic attacking of the bound dioxygen by the trim of its phenyl ring,and the residue Phe381 plays a key role in orienting the phenyl ring.Kinetic study on the F381 A mutant reveals that the HPPD-HPPA complex observed in the crystal structure should be an intermediate of the substrate transportation instead of the pre-reactive complex.More importantly,the binding mode of the HPPA in this complex is shared with several well-known HPPD inhibitors,suggesting that these inhibitors resist the association of dioxygen(and exert their inhibitory roles)in the same way as the HPPA.The present study provides insights into the inhibition mechanism of HPPD inhibitors.

关 键 词：4-Hydroxyphenylpyruvate dioxygenase QM/MM calculation Potential surface scan Substrate self-inhibition 

分 类 号：O621.251[理学—有机化学]