化学
立体化学
分子动力学
立体选择性
突变体
底物特异性
活动站点
过渡状态
基质(水族馆)
非对映体
酶
计算化学
催化作用
生物化学
基因
生物
生态学
作者
Elizabeth L. Noey,Nidhi Tibrewal,Gonzalo Jiménez‐Osés,Sílvia Osuna,Jiyong Park,Carly M. Bond,Duilio Cascio,Jack Liang,Xiyun Zhang,Gjalt W. Huisman,Yi Tang,K. N. Houk
标识
DOI:10.1073/pnas.1507910112
摘要
Significance Ketoreductases are the most commonly used enzymes in industrial pharmaceutical synthesis. We investigated the nature of enantioselectivity in closely related mutant ketoreductases that reduce almost-symmetrical 3-oxacyclopentanone and 3-thiacyclopentanone, which are difficult to reduce enantioselectively by other means. We present the efficiencies of select variants and their crystallographic structures. Our experimental and theoretical studies reveal how mutations modulate the stereoselectivity of the reduction. Molecular dynamics simulations of the Michaelis–Menten and transition state-bound complexes were used to rationalize the observed stereochemical outcomes. We discovered that the closed conformation of the flexible substrate binding loop is likely the catalytically active one imparting the stereochemical preferences. Our molecular dynamics approach reveals how each enzyme stabilizes the diastereomeric transition structures by altering the active site size.
科研通智能强力驱动
Strongly Powered by AbleSci AI