A molecular dynamics and computational study of human KAT3 involved in KYN pathway  

作　　者：XU Yu ZHENG QingChuan YU LiYing ZHANG HongXing SUN ChiaChung 

机构地区：[1]State Key Laboratory of Theoretical and Computational Chemistry, Institute of Theoretical Chemistry, Jilin University

出　　处：《Science China Chemistry》2013年第4期514-523,共10页中国科学（化学英文版）

基　　金：supported by the National Natural Science Foundation of China;Specialized Research Fund for the Doctoral Program of Higher Education;Specialized Fund for the Basic Research of Jilin University (20903045, 20573042, 20070183046,200810018)

摘　　要：Kynurenine aminotransferases （KATs） catalyze the transamination of kynurenine （KYN） pathway and endogenous KYNs have been suggested to highly correlate to abnormal brain diseases. HKAT3 is a key member of KAT family, while the binding mechanism of KYN and cofactor with HKAT3 has not been determined yet. In this study, we focus on the structure-function relationship among KYN, cofactor and HKAT3. The binding models of KYN complex and KYN＆cofactor complex were ob- tained and were studied by molecular dynamics （MD） simulations. We identified several critical residues and influence of conformational changes in human kynurenine aminotransferase 3 （HKAT3） complexes. The cofactor may contribute largely not only to the catalysis, but also to the binding. In addition, a hypothesis is proposed that a strong hydrophobic interaction between Tyr159 and Lys280 may influence the binding mode and the binding region of the substrate and the cofactor. Our re- suits will be a good starting point for further determination of the biological role.Kynurenine aminotransferases (KATs) catalyze the transamination of kynurenine (KYN) pathway and endogenous KYNs have been suggested to highly correlate to abnormal brain diseases. HKAT3 is a key member of KAT family, while the binding mechanism of KYN and cofactor with HKAT3 has not been determined yet. In this study, we focus on the structure-function relationship among KYN, cofactor and HKAT3. The binding models of KYN complex and KYN&cofactor complex were obtained and were studied by molecular dynamics (MD) simulations. We identified several critical residues and influence of conformational changes in human kynurenine aminotransferase 3 (HKAT3) complexes. The cofactor may contribute largely not only to the catalysis, but also to the binding. In addition, a hypothesis is proposed that a strong hydrophobic interaction between Tyr159 and Lys280 may influence the binding mode and the binding region of the substrate and the cofactor. Our results will be a good starting point for further determination of the biological role.

关 键 词：kynurenine （KYN） kynurenine aminotransferases （KATs） ^-~ interaction molecular dynamic （MD） simulation interaction energy 

分 类 号：R-332[医药卫生]