OXIDATION OF OMEGA-OXO FATTY-ACIDS BY CYTOCHROME P450(BM-3) (CYP102)

Cytochrome P450 enzymes oxidize aldehydes either to the corresponding acid or, via a decarboxylation mechanism, to an olefin one carbon shor ter than the parent substrate, To explore the factors that control par titioning between these two pathways, we have examined the cytochrome P450(BM-3) (CYP102)-catalyzed oxidation of fatty acids with a terminal aldehyde group. P450(BM-3) oxidizes 18-oxooctadecanoic, 16-oxohexadec anoic, 14-oxotetradecanoic, and 12-oxododecanoic acids exclusively to the corresponding alpha,omega-diacids, The rates of these oxidations d ecrease in the order C-16 > C-18 similar or equal to C-14 > C-12. NO k inetic isotope effect is observed nor is the catalytic outcome altered when the aldehyde hydrogen is replaced by a deuterium in 16-oxohexade canoic acid, The only product observed with 16-oxohexadecanoic acid is the diacid even when a 13,14-double bond or 15-methyl groups, substit utions that should stabilize the proposed radical intermediate generat ed by decarboxylation, are present. The oxidation of 16-oxohexadecanoi c acid is not supported by H2O2. The results demonstrate that aldehyde oxidation by cytochrome P450(BM-3) is insensitive to changes in subst rate structure expected to stabilize the transition state for decarbox ylation. Decarboxylation, in contrast to the oxidation of aldehydes to acids, depends on specific substrate-protein interactions and is enzy me-specific. (C) 1996 Academic Press, Inc.