Other Modes of P450 Heme Degradation and Protein Denaturation

Other Modes of P450 Heme Degradation and Protein Denaturation 

The inactivation of CYP2B4 by aldehydes such as citral (an a,P unsaturated terpenoid aldehyde), and other 2iromatic aldehydes (cinnamaldehyde, benzaldehyde, and 3-phenylpropionaldehyde) is accompanied by bleaching of the heme chro-mophore that is not prevented by catalase, superoxide dismutase, epoxide hydrolase, GSH, or ascorbic acid . The corresponding values revealed that saturated aldehydes are generally 

Interestingly, incubation of CYP2B4 with artificial oxidants and aldehydes yielded different heme adducts. 3-Phenylpropionaldehyde yielded an adduct with a mass equal to that of native 

Similar studies with f/-ans-4-hydroxy-2-none-nal (HNE, a cytotoxic byproduct of biological membrane lipid peroxidation), indicate that it is also metabolically activated by CYP2B1 and -2B4 to a reactive species that binds irreversibly to their prosthetic heme . Unlike the mechanism-based inactivation by aromatic aldehydes, strucmral analyses of the corresponding heme adduct (MW 770) revealed that the reaction proceeds without deformylation and involves an acyl carbon radical that partitions between addition to the heme and formation of the carboxylic acid . Together these findings suggest that the P450-mediated metabolic activation of aldehydes is a versatile process wherein the enzyme may be inactivated via mechanistically diverse heme modifications. 

The links between formation of an iron-alkyl complex and irreversible destruction of the heme moiety have not been forged, but model studies with diaryl- and carbethoxy-substituted carbene complexes suggest that the halogenated carbenes may shift to form a bond with a nitrogen of the porphyrin. The resulting A -haloaIkyl adduct are likely to undergo water-dependent hydrolysis and might therefore not be detected by the methods used to isolate other A -alkyl porphyrins. However, the formation of alternative reactive species that attack the protein or the heme cannot be ruled out. 

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