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Vol. 26, Issue 12, 1190-1193, December 1998

Multiple Activated Oxygen Species in P450 Catalysis
Contributions to Specificity in Drug Metabolism1

Minor J. Coon, Alfin D. N. Vaz, Dermot F. McGinnity, and Hwei-Ming Peng

Department of Biological Chemistry, Medical School, The University of Michigan

A hypervalent iron-oxene species has been widely proposed as the "active oxygen" in cytochrome P450 (P450)-catalyzed reactions. We recently examined the effect of mutation of the highly conserved threonine residue in P450s 2B4 and 2E1 to alanine, a change that is believed to interfere with proton delivery to the active site, and have determined the change in rates of deformylation of aldehydes, epoxidation of olefins, and hydroxylation of various substrates. The results support the concept that three distinct oxidants are functional in P450 catalysis: nucleophilic peroxo-iron, nucleophilic or electrophilic hydroperoxo-iron, and electrophilic oxenoid-iron. The occurrence of multiple oxidizing species may contribute to the remarkable versatility of the P450 family of isozymes in the modification of drugs and other substrates. Furthermore, the relative concentrations of these oxidants in a particular P450 isozyme may contribute to substrate specificity and govern the type of reaction catalyzed.

1   This article is dedicated to Anthony Lu for his pioneering contributions to the field of cytochrome P450 and its relevance to drug metabolism and design, and for his friendship.

Copyright © 1998 by The American Society for Pharmacology and Experimental Therapeutics


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Copyright © 1998 by the American Society for Pharmacology and Experimental Therapeutics.