Mechanisms of Cytochrome P450 Reactions

F. Peter Guengerich* and Emre M. Isin

Department of Biochemistry, Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville,
Tennessee 37232-0146, U.S.A.,
Biotransformation Section, Department of Discovery DMPK & Bioanalytical Chemistry, AstraZeneca R & D Mölndal, SE-431 83 Mölndal, Sweden
Telephone: 1-615-322-2261; Fax: 1-615-322-3141

The cytochrome P450 enzymes (P450s) catalyze a number of different reactions using a basic chemical template. The course of events follows the order of substrate binding, 1-electron reduction, O2 binding, a second 1-electron reduction, and then a series of less well-defined steps understood as protonation, hemolytic scission of the O–O bond to yield an active perferryl FeO species (depicted as FeO3+), reaction with the substrate, and release of the product, although the point should be made that the sequence of some of the events may vary. The chemical events are generally applicable to most of the oxidative reactions. Exactly why rates of individual P450 reactions vary is still not clear. The basic P450 reactions include C-hydroxylation, heteroatom oxygenation, heteroatom release (dealkylation), epoxide formation, and 1,2-migration. However, P450 enzymes also use variations of the basic chemistry to catalyze what appear to be a myriad of unusual reactions, including reductions, isomerizations, and oxidative coupling.

Keywords: Cytochrome P450, CYP, oxidation reactions, chemical coupling, biosynthesis, antibiotics