Bacterial Cytochrome P-450 Monooxygenases

Abstract

The P450 cytochromes are a distinct class of heme thiolate proteins characterized by interactions with organic compounds and carbon monoxide that produce unique spectroscopic properties (1). Together with associated redox components, the P450 heme proteins function as monooxygenases, catalyzing the two-electron reduction of dioxygen to form a molecule of water and an activated oxygen atom (2). The subsequent transfer of this oxygen atom to hydrocarbon substrates constitutes a major pathway of oxygenase activity in biological systems (1–7). Eukaryotes in particular are characterized by a wide distribution of organ and organelle specific P450 monooxygenases, whose diversification is further amplified by multiple isozymes of overlapping substrate specificity, for example in mammalian hepatic tissue. The broad range of substrate selectivity exhibited by P450 cytochromes parallels their involvement in many different types of biological functions. In the endoplasmic reticulum of hepatic cells, P450 cytochromes participate in the detoxification of xenobiotic compounds, such as the hydroxylation of the pharmaceutical sedative phenobarbital. Other liver microsomal P450 systems will catalyze the activation of carcinogenic DNA-alkylating agents, as represented by the epoxidation of benzo[a]pyrene derivatives. In contrast, mitochondrial P450 monooxygenases of the adrenal cortex mediate a cascade of anabolic pathways in the biosynthesis of regulatory steroid hormones, such as hydrocortisone.