Monoxygenases, cytochrome

O Keefe DP, PA Harder (1991) Occnrrence and biological function of cytochrome P-450 monoxygenase in the actinomycetes. Mol Microbiol 5 2099-2105. 

Tetraethyl and tetramethyl lead under oxidative dealkylation metabolize to the highly neurotoxic metabolites, triethyl and trimethyl lead, respectively. In the liver, the reaction is catalyzed by a cytochrome P-450 dependent monoxygenase system (Kimmel et al. 1977). Complete oxidation of alkyl lead to inorganic lead also occurs (Bolanowska 1968). 

Pinto, A., Abraham, N. G., Mullane, K. M., Cytochrome P450-dependent monoxygenase activity and endothelial-dependent relaxations induced by arachidonic acid. J. Pharmucol. Exp. Ther. 236 (1986),... 

Fig. 2. Schematic representation of paclitaxel biosynthesis. Dimethylallyl-diphosphate and isopentenyl-diphosphate are condensed through geranylgeranyl diphosphate synthase activity to render geranylgeranyl-diphosphate (GGPP). GGPP is converted into taxa-4(5), 11 (12)-diene in a reaction catalyzed by the taxane synthase (TS). A series of reactions catalyzed by cytochrome P450 monoxygenases lead to the production of a taxane intermediate that is further converted to baccatin III through enzymes-driven oxidation and oxetane ring formation. The side chain moiety of paclitaxel is derived from L-phenylalanine. Three consecutive arrows mean multiple steps. Ac, acetyl Bz, benzoyl.

Oxidation is by far the most important Phase I metabolic reaction. One of the main enzyme systems involved in the oxidation of xenobiotics appears to be the so called mixed function oxidases or monooxygenases, which are found mainly in the smooth endoplasmic reticulum of the liver but also occur, to a lesser extent, in other tissues. These enzymes tend to be nonspecific, catalysing the metabolism of a wide variety of compounds (Table 9.2). Two common mixed function oxidase systems are the cytochrome P-450 (CYP-450) and the flavin monoxygenase (FMO) systems (Appendix 12). The overall oxidations of these systems take place in a series of oxidative and reductive steps, each step being catalysed by a specific enzyme. Many of these steps require the presence of molecular oxygen and either NADH or NADPH as co-enzymes. 

Testosterone has been used as a model substrate for different cytochrome P450 monoxygenase activities. As a result of these oxidation reactions, multiple chemically related products are formed. In the assay developed for this activity, seven products are distinguished. 

The mechanism proposed for the 4-electron reduction of dioxygen to water by cytochrome c oxidase may be similar to that proposed for the monoxygenase enzymes, the cytochromes P450, as well as the peroxidases and catalase, all of which are discussed iu Sectiou 9 below. DFT calculations of the mechanism of the bond cleavage step, specifically addressing CcO, have been reported and an excellent overview provided. ... 

Gelb, M. H., Heimbrook, D. C., Malkonen, P., and Sligar, S. G. Stereochemistry and deuterium isotope effects in camphor hydroxylation by the cytochrome P450cam monoxygenase system. Biochemistry 21, 370-377 (1982). 

Further on down the respiratory chain from hemoglobin lie the monoxygenase enzymes, cytochromes P450, which perform the function of selectively oxidizing organic materials to usable or excretable... 

Andersson, T., M. Pesonen, and C. Johansson. 1985. Differential induction of cytochrome P-450-dependent monoxygenase, epoxide hydrolase, glutathione transferase and UDP glucuronyltransferase activities in the liver of the rainbow trout by 3-naphthoflavone or Clophen A50. Biochem. Pharmacol. 34 3309-3314. 

Masuda Y, Yasoshima M, Nakayama N. 1986. Early, selective and reversible suppression of cytochrome P-45 0-dependent monoxygenase of liver microsomes following the administration of low doses of carbon disulfide in mice. Biochem Pharmacol 35 3941-3947. 

Nebert, D.W., J.R. Robinson, and H. Kon (1973). Genetically mediated differences in monoxygenase activities and spin state of cytochrome P450 iron from rabbit, rat, and mouse liver. J. Biol. Chem. 248, 7637-7647. 

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