Modified fatty acids as cytochrome P450 substrates

Fatty acids are metabolized by a number of different P450s.(1) We have utilized the ability of these moieties to carry a number of functional groups into the enzyme active site in order to investigate the mechanism of P450 catalyzed oxidation reactions. To date, these functional groups have included additional alkyl substituents, halides(2), thioethers, alcohols, diols(3) and cyclopropyl rings(4) The product profiles from these reactions have revealed a subtle interplay of steric and electronic effects that determine the nature and regiochemistry of the oxidative transformation catalyzed by the P450. Additionally, the cyclopropyl substituted fatty acids present the possibility of distinguishing among concerted, radical and cationic mechanisms for hydrocarbon hydroxylation.(4,5) Recent results suggest the enzyme/substrate pair may determine the mechanistic pathway followed.