Fundamental reaction pathways for cytochrome P450-catalyzed 5'-hydroxylation and N-demethylation of nicotine.

ABSTRACT: The reaction pathways for 5'-hydroxylation and N-demethylation of nicotine catalyzed by cytochrome P450 were investigated by performing a series of first-principle electronic structure calculations on a catalytic reaction model system. The computational results indicate that 5'-hydroxylation of nicotine occurs through a two-state stepwise process, that is, an initial hydrogen atom transfer from nicotine to Cpd I (i.e., the HAT step) followed by a recombination of the nicotine moiety with the iron-bound hydroxyl group (i.e., the rebound step) on both the high-spin (HS) quartet and low-spin (LS) doublet states. The HAT step is the rate-determining one. This finding represents the first case that exhibits genuine rebound transition state species on both the HS and the LS states for C(alpha)-H

SUBMITTER: Li D 

PROVIDER: S-EPMC2909651 | biostudies-literature | 2010 Jul

REPOSITORIES: biostudies-literature