Catalytic mechanism of cytochrome P450 for N-methylhydroxylation of nicotine: reaction pathways and regioselectivity of the enzymatic nicotine oxidation.

ABSTRACT: The fundamental reaction mechanism of cytochrome P450 2A6 (CYP2A6)-catalyzed N-methylhydroxylation of (S)-(-)-nicotine and the free energy profile have been studied by performing pseudobond first-principles quantum mechanical/molecular mechanical (QM/MM) reaction-coordinate calculations. In the CYP2A6-(S)-(-)-nicotine binding structures that allow for 5'-hydroxylation, the N-methyl group is also sufficiently close to the oxygen of Cpd I for the N-methylhydroxylation reaction to occur. It has been demonstrated that the CYP2A6-catalyzed N-methylhydroxylation reaction is a concerted process involving a hydrogen-transfer transition state on both the quartet and the doublet states. The N-methylhydroxylation reaction proceeds mainly in the doublet state, since the free energy barriers on the dou

SUBMITTER: Li D 

PROVIDER: S-EPMC3619389 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature