Department of Chemistry and Biochemistry , Florida International University , 11200 8th Street , Miami , Florida 33199 , United States.
J Phys Chem B. 2018 Aug 16;122(32):7828-7838. doi: 10.1021/acs.jpcb.8b04279. Epub 2018 Aug 8.
This paper examines the influence of the proximal pockets of cytochrome P450 and chloroperoxidase (CPO) on the relative favorability of catalytic epoxidation and allylic hydroxylation of olefins, a type of alkene oxidation selectivity. The study employs quantum mechanical models of the active site to isolate the proximal pocket's influence on the barrier for the selectivity-determining step for each reaction, using cyclohexene and cis-β-methylstyrene as substrates. The proximal pocket is found to preference epoxidation by 2-5 kcal/mol, the largest value being for CPO, converting the active heme-thiolate moiety from being intrinsically hydroxylation-selective to being intrinsically epoxidation-selective. This theoretical study, the first to correctly predict these enzymes' preference for epoxidation of allylic substrates, strongly suggests that the proximal pocket is the key determinant of alkene oxidation selectivity. The selectivity for epoxidation can be rationalized in terms of the proximal pocket's modulation of the thiolate's electron "push" and consequent influence on the heme redox potential and the basicity of the trans ligand.
本文研究了细胞色素 P450 和氯过氧化物酶（CPO）的近端口袋对烯烃氧化选择性中催化环氧化和烯丙基羟化相对有利性的影响。该研究使用活性位点的量子力学模型，通过以环己烯和顺-β-甲基苯乙烯为底物，分离近端口袋对每个反应的选择性决定步骤的势垒的影响。发现近端口袋偏爱环氧化，其能量差为 2-5 kcal/mol，其中 CPO 的差值最大，将活性血红素-硫醇部分从固有羟化选择性转变为固有环氧化选择性。这项理论研究首次正确预测了这些酶对烯丙基底物环氧化的偏好，强烈表明近端口袋是烯烃氧化选择性的关键决定因素。可以根据近端口袋对硫醇的电子“推动”的调节以及对血红素氧化还原电位和反位配体碱性的影响来解释环氧化的选择性。
