Progress in theoretical study on the catalytic mechanism of cytochrome P450 2E1

Cytochrome P450 enzyme is an important biocatalyst, which can promote C-H bond hydroxylation, C = C double bond epoxidation, sulfur, nitrogen, phosphorus heteroatom oxidation and other chemical reactions Cytochrome P450 2E1 is one of the most important P450 enzymes in human body, which is closely related to the metabolism of drugs and exogenous and endogenous compounds The microsomal oxidation of ethanol containing P450 2E1 enzyme is an important pathway of alcohol metabolism in human body, so P450 2E1 has been widely concerned However, the mechanism of P4502E1 catalyzed ethanol oxidation is still controversial because ethanol can be oxidized by breaking its O-H or α - C-H bonds The theoretical study on the mechanism of P450 2E1 catalyzing ethanol oxidation can not only clarify the specific mechanism of P450 2E1 participating in alcohol metabolism in human body, but also help to understand the mechanism of P450 enzyme catalyzing small molecule activation reaction Li chunsen, research group of Fujian Institute of material structure and State Key Laboratory of structural chemistry, Chinese Academy of Sciences, supported by general program of National Natural Science Foundation, Postdoctoral Science Foundation and special project of strategic leading science and technology of Chinese Academy of Sciences, cooperated with Walter Thiel, Professor of Mapu Coal Research Institute, Germany, and adopted combined MD simulation and QM / mm calculation method to study cytochrome P450 The exact reaction mechanism of 2E1 catalyzing ethanol oxidation was studied by theoretical calculation, and new progress was made The results show that thr303 residues near P450 2E1 active site have a crucial effect on ethanol oxidation: MD simulation results show that the OH group of thr303 side chain fixes ethanol molecules in a specific configuration near the active site through hydrogen bonding; QM / mm calculation shows that P450 is based on thr303 as a substrate guidance 2E1 catalyzed ethanol oxidation is initiated by the hydrogen extraction of ethanol O-H bond, and then the product acetaldehyde is formed by the hydrogen extraction of α - C-H bond The activation of α - C-H bond in the second step is the decisive step of the reaction, which reasonably explains the dynamic isotope phenomenon in the experiment, that is, P450 is sensitive to the isotope effect of ethanol oxidation on α - C-H site This theoretical calculation shows that the thr residue near the active site of P450 enzyme not only acts as a proton carrier in the process of P450 enzyme oxygen activation, but also regulates the conformation of the small molecules of the substrate combined with the active center of P450 enzyme through the hydrogen bond of its side chain OH group, thus affecting the reaction mechanism of these substrates and realizing the high efficiency and selectivity of P450 enzyme to the substrate Catalytic reaction, so as to expand people's understanding of P450 catalytic reaction mechanism, and provide a new idea for the artificial synthesis of similar P450 catalysts to achieve related catalytic reactions The above work was published in ACS Catalysis (ACS Catal 2019, 94892-4901) The first author of the article is Lu Qianqian, a postdoctoral researcher.