细胞色素P450蛋白酶对花生四烯酸羟基化和环氧化的理论研究

Theoretical Study Cytochrome P450 Catalyzing Arachidonic Acid by Hydroxylation and Epoxidation

花生四烯酸是人体内重要不饱和脂肪酸,它的代谢产物对人体具有重要的生理功能.细胞色素P450酶作为人体内重要的一种氧化还原酶,它能够代谢花生四烯酸产生羟基二十碳四烯酸(HETE)和表氧二十碳三烯酸(EET).通过量子化学中的密度泛函方法能够从原子水平上研究P450酶对花生四烯酸的催化过程.结果表明,P450酶羟基化花生四烯酸包括氢提取和回弹的两个步骤.氢提取是整个反应的决速步骤,而且羟基化的过程在两种自旋态下都可以进行.P450酶环氧化花生四烯酸的过程只通过一个过渡态就得到产物,从能量角度上看,低自旋态的反应更容易进行.

Arachidonic acid is an important unsaturated fatty acid in human body. The metabolites of arachidonic acid are important for physiological functions. Cytochrome P450 enzymes is an vital oxidoreductase in human body,which can catalyze arachidonic acid by hydroxylation and epoxidation to produce HETEs and EETs,respectively. Density functional theory was employed to study the catalytic process at the atomic level. The results showed that the hydroxylation of arachidonic acid includes two steps：the hydrogen abstract process and rebound process, and the hydrogen abstract process is the rate-determining step of the hydroxylation reaction. The calculations showed that hydroxylation can process in both high spin state and low spin state. In epoxidation reaction,P450 catalyzing arachidonic acid only includes a transition state to produce the product. The energy suggests that the low spin state reaction is more favorable.