Mechanism of the cytochrome P-450 catalyzed isomerization of hydroperoxides.

Abstract

The interactions of hydroperoxides with cytochrome P-450 have been studied extensively (O’Brien, 1982; Sligar et al., 1984). It is well known that these compounds can donate an oxygen to the ferric form of P-450. The resulting activated form of the enzyme can oxidize many substrates with results similar to those of NADPH/O2-supported P-450 oxidations. Mechanistic details of the O-O bond cleavage step and the nature of the oxidant remain unsettled issues. Homolytic cleavage would produce an alkoxy radical and an iron-coordinated hydroxyl radical similar to peroxidase Compound II (equation 1, where Fe represents the heme iron of P-450). Heterolytic cleavage of the O-O bond would produce the alcohol and an iron-oxo species analogous to peroxidase Compound I (equation 2). Much of the early work in this area suggests that homolysis is the principal result when hydroperoxides interact with P-450. For example, Griffin (1980) successfully trapped a methyl radical from the microsomal decomposition of cumene hydroperoxide (COON). This species is produced when the cumyloxy radical undergoes β-scission. Blake and Coon (1981) invoked homolysis to explain the results of structure-activity relationships on the benzylic hydroxylation of substituted toluenes by rabbit liver P-450LM2 that were supported by analogs of COOH. According to the mechanism proposed, the cumyloxy radical is the oxidant that abstracts H• from the substrate. The resulting carbon-centered radical then interacts with (FeOH)3+ forming the benzylic alcohol and the native enzyme. More recent work with P-450 and peroxyphenylacetic acid demonstrated that peroxy compounds can undergo both homolytic and heterolytic scission of the O-O bond. McCarthy and White (1983) provided evidence that hydroxylations of cosubstrates in the P-450-peroxyacid system were a consequence of heterolysis, and that (FeO)3+ was the oxidant. Recently, it was reported that P-450 catalyzes both types of O-O bond cleavage, and that the actual mechanism is dependent on the structure of the peroxy compound (Lee and Bruice, 1985).KeywordsCumene HydroperoxideHomolytic CleavageHeterolytic CleavagePeroxy CompoundMethylmagnesium IodideThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.