Multiple activated oxygen species in P450 catalysis - Contributions to specificity in drug metabolism

A hypervalent iron-oxene species has been widely proposed as the "active ox ygen" in cytochrome P450 (P450)-catalyzed reactions. We recently examined t he effect of mutation of the highly conserved threonine residue in P450s 2B 4 and 2E1 to alanine, a change that is believed to interfere with proton de livery to the active site, and have determined the change in rates of defor mylation of aldehydes, epoxidation of olefins, and hydroxylation of various substrates. The results support the concept that three distinct oxidants a re functional in P450 catalysis: nucleophilic peroxo-iron, nucleophilic or electrophilic hydroperoxo-iron, and electrophilic oxenoid-iron. The occurre nce of multiple oxidizing species may contribute to the remarkable versatil ity of the P450 family of isozymes in the modification of drugs and other s ubstrates. Furthermore, the relative concentrations of these oxidants in a particular P450 isozyme may contribute to substrate specificity and govern the type of reaction catalyzed.