Understanding the cooperative effects in the catalysis of homodimeric fluoroacetate dehalogenase  

作　　者：Ke-Wei Chen Jia-Nan Chen Jun Zhang Chao Wang Tian-Yu Sun Yun-Dong Wu 

机构地区：[1]Key Laboratory of Computational Chemistry and Drug Design,State Key Laboratory of Chemical Oncogenomic,School of Chemical Biology and Biotechnology,Peking University Shenzhen Graduate School,Shenzhen 518055,China [2]Institute of Chemical Biology,Shenzhen Bay Laboratory,Shenzhen 518132,China [3]College of Chemistry and Molecular Engineering,Peking University,Beijing 100871,China [4]Changping Laboratory,Beijing 102200,China

出　　处：《Science China Chemistry》2024年第7期2382-2391,共10页中国科学（化学英文版）

基　　金：supported by the Key-Area Research and Development Program of Guangdong Province(2020B0101350001);the Shenzhen Fundamental Research Program(GXWD2020123116580700720200812124825001);the Shenzhen Science and Technology Program(RCBS20210706092258097);supported by the Shenzhen Bay Laboratory Supercomputing Center。

摘　　要：Fluoroacetate dehalogenases(FAcD),a homodimeric enzyme,catalyzes the conversion of fluoroacetic acid to glycolic acid(GoA).It has been proved that the enzyme has a half-of-the-site reactivity.Namely,its catalytic(C)subunit converts the first substrate to a covalent intermediate;then,the non-catalytic(NC)subunit binds a second substrate and promotes the conversion of the intermediate in the C subunit into the final product.After the release of the product,the C subunit becomes the NC subunit,and the previous NC subunit becomes the C subunit.To elucidate the detailed mechanism behind this cooperative catalysis,we have conducted microsecond-scale MD simulations along the reaction pathway.The simulations indicate that the substrate in the NC subunit induces W185 and Y141 adopting an open conformation in the C subunit.The opening of W185(C)facilitates the entry of catalytic water,enhancing the catalytic activity for product formation,while the opening of Y141(C)creates an unfavorable environment for product binding,promoting its release.An interaction network analysis reveals that the substrate in the NC subunit can induce conformational changes through a conserved water chain at the interface.

关 键 词：enzyme catalysis molecular dynamics cooperative effect pre-reaction state 

分 类 号：TQ426.97[化学工程]