STEREOSPECIFIC ACTIVATION OF THE PROCARCINOGEN BENZO[ALPHA]PYRENE - A PROBE FOR THE ACTIVE-SITES OF THE CYTOCHROME-P450 SUPERFAMILY

It has been established previously that the stereochemistry of epoxidation of the procarcinogen benzo[a]pyrene determines the potency of the ultimate carcinogen. Herein we report that seven human P450s, five rodent P450s, and two bacterial P450s all convert B[a]P to the most potent carcinogenic stereoisomer. This is in contrast to most P450-catalyzed reactions, for which the various P450 enzymes often differ in both regioselectivity and stereoselectivity. This is likely due to the large size of the substrate molecule and its constraints in the active sites. Smaller substrates that can rotate more freely in the active site may be expected to have greater variations in binding orientations and therefore greater differences in stereoselectivities. Molecular mechanics is used to determine the specific amino acids responsible for the stereochemical outcome. Molecular dynamics is then used to strengthen the hypothesis that a single helical region, one that is likely to be conserved in all P450s, plays a primary role in determining the stereoselectivity of the reaction.