title: Multi-step oxidations catalyzed by cytochrome P450 enzymes: Processive vs. distributive kinetics and the issue of carbonyl oxidation in chemical mechanisms.
abstract: Catalysis of sequential oxidation reactions is not unusual in cytochrome P450 (P450) reactions, not only in steroid metabolism but also with many xenobiotics. One issue is how processive/distributive these reactions are, i.e., how much do the "intermediate" products dissociate. Our work with human P450s 2E1, 2A6, and 19A1 on this subject has revealed a mixture of systems, surprisingly with a more distributive mechanism with an endogenous substrate (P450 19A1) than for some xenobiotics (P450s 2E1, 2A6). One aspect of this research involves carbonyl intermediates, and the choice of catalytic mechanism is linked to the hydration state of the aldehyde. The non-enzymatic rates of hydration and dehydration of carbonyls are not rapid and whether P450s catalyze the reversible hydration is unknown. If carbonyl hydration and dehydration are slow, the mechanism may be set by the carbonyl hydration status.
authors.affiliation: Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, TN 37232-0146, USA. f.guengerich@vanderbilt.edu
authors.forename: F Peter
authors.initials: FP
authors.lastname: Guengerich
authors.forename: Christal D
authors.initials: CD
authors.lastname: Sohl
authors.forename: Goutam
authors.initials: G
authors.lastname: Chowdhury
mesh_terms: D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D001141:Aromatase / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D010084:Oxidation-Reduction; D013379:Substrate Specificity
chemical_list: D000447:Aldehydes; D003577:Cytochrome P-450 Enzyme System; D001141:Aromatase
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