西亚试剂：Catalytic Mechanism of Cytochrome P450 for 5′-Hydroxylation

Catalytic Mechanism of Cytochrome P450 for 5′-Hydroxylation of Nicotine: Fundamental Reaction Pathways and Stereoselectivity

Dongmei Li, Xiaoqin Huang, Keli Han, and Chang-Guo Zhan

A series of computational methods were used to study how cytochrome P450 2A6 (CYP2A6) interacts with (S)-(?)-nicotine, demonstrating that the dominant molecular species of (S)-(?)-nicotine in CYP2A6 active site exists in the free base state (with two conformations, SRt and SRc), despite the fact that the protonated state is dominant for the free ligand in solution. The computational results reveal that the dominant pathway of nicotine metabolism in CYP2A6 is through nicotine free base oxidation. Further, first-principles quantum mechanical/molecular mechanical free energy (QM/MM-FE) calculations were carried out to uncover the detailed reaction pathways for the CYP2A6-catalyzed nicotine 5′-hydroxylation reaction. In the determined CYP2A6–(S)-(?)-nicotine binding structures, the oxygen of Compound I (Cpd I) can abstract a hydrogen from either the trans-5′- or the cis-5′-position of (S)-(?)-nicotine. CYP2A6-catalyzed (S)-(?)-nicotine 5′-hydroxylation consists of two reaction steps, that is, the hydrogen tra...