Contributions to Specificity in Drug Metabolism1
Abstract
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.
Footnotes
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Send reprint requests to: Dr. Minor J. Coon, Department of Biological Chemistry, Medical School, The University of Michigan, Ann Arbor, MI 48109-0606. e-mail: mjcoon{at}umich.edu
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↵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.
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This research was supported by grants DK-10339 and AA-06221 from the National Institutes of Health.
- Abbreviation used is::
- P450
- cytochrome P450
- The American Society for Pharmacology and Experimental Therapeutics
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