Epoxidation by cytochrome

Ortiz de Montellano PR, JA Eruetel, JR Collins, DL Camper, GH Loew (1991) Theoretical and experimental analysis of the absolute stereochemistry of ci5-[l-methylstyrene epoxidation by cytochrome P-450,j . JAm Chem Soc 113 3195-3196. 

Scheme 13.3 Olefinic compounds that form mutagenic epoxides by cytochrome P450 oxidation.

However, most of the debate in this area has been over the mechanism of epoxidation by cytochrome P450 (c-P450) and its analogs. C-P450 is a monooxygenase whose active center is an iron(III) porphyrin136 its catalytic cycle is shown in Scheme 53137. 

L. L. Shipman, in Polynuclear Aromatic Hydrocarbons, R. Freudenthal and P. W. Jones, Eds., Raven Press, New York, 1976. Ab Initio Quantum Mechanical Characterization of the Ground Electronic State of Benzo[ ]pyrene. Implications for the Mechanism of Polynuclear Aromatic Hydrocarbon Oxidation to Epoxides by Cytochrome P-450. 

Figure 15. The catalytic-binding-site model predicts that opposite enantiotopic faces of bcnz(a)anthracenc (BA) must be epoxidized by cytochrome P450c to produce the observed stereochemical outcome. Formation of the opposite enantiomers in either case would require the hydrocarbon to be bound in such a fashion that at least one ring would occupy a restricted region.

Figure 2 Benzo[a]pyrene is metabolized highly stereoseiectively to the ultimate carcinogen (+)-benzo[a]pyrene- ntf-7R,8S-dihydriol-9S,10R-epoxide by cytochrome P450-IA1 and epoxide hydrolase. (From Jerina et al., 1985.)...

Shaik, S., S.P. De Visser, F. Ogliaro, H. Schwarz, and D. Schrder (2002). Two-state reactivity mechanisms of hydroxylation and epoxidation by cytochrome P-450 revealed by theory. Curr. Opin. Chem. Biol. 6, 556-567. 

De Visser, S.P., D. Kumar, and S. Shaik (2004). How do aldehyde side products occur during alkene epoxidation by cytochrome P450 Theory reveals a state-specific multi-state scenario where the high-spin component leads to all side products. J. Inorg. Biochem. in press. 

Groves, J.T., G.E. Avaria-Neisser, K.M. Fish, M. Imachi, and R.L. Kuczkowski (1986). Hydrogen-deuterium exchange dming propylene epoxidation by cytochrome P450. J. Am. Chem. Soc. 108, 3837-3838. 

HanzHk, R.P. and G.O. Shearer (1978). Secondary deuterium isotope effects on olefin epoxidation by cytochrome P450. Biochem. Pharmacol. 27, 1441-1444. 

Acrylamide is metabolised to an 1,2-epoxide by cytochrome P4so-dependent (CYP) monooxygenases. Due to the large ring strain associated with the three-membered ring epoxides are reactive molecules. 

A series of reactions has been reported that is taken to be the metabolic pathway for conversion of benzene to cancer-inducing metabolites. Benzene is epoxidized by cytochrome P-450 to give 192 and then enzymatically hydrolyzed to 193. This intermediate is converted to catechol (34), which in turn can be converted to phenol (19). Phenol can be converted to hydroquinone (192), which gives rise to benzoquinone (201937) and 1,2,4-trihydroxybenenze (194). Catechol can be oxidized enzymatically to the 1,2-quinone (orf/io-quinone, 195). 

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