Amine oxidase, mixed function

Amine oxidase, mixed function, 153-154 Amino acid(s)... 

For foreign compounds, the majority of oxidation reactions are catalyzed by monooxygenase enzymes, which are part of the mixed function oxidase (MFO) system and are found in the SER (and also known as microsomal enzymes). Other enzymes involved in the oxidation of xenobiotics are found in other organelles such as the mitochondria and the cytosol. Thus, amine oxidases located in the mitochondria, xanthine oxidase, alcohol dehydrogenase in the cytosol, the prostaglandin synthetase system, and various other peroxidases may all be involved in the oxidation of foreign compounds. 

Kerklaan, P.R.M.. Bouter, S., Zijlstra, J. A. Mohn, GR. (1986) The effect of mixed-function oxidase and amine oxidase inhibitors on the activation of dialkylnitrosamines and 1,2-dimethylhydrazine to bacterial mutagens in mice. J. Cancer Res. din. Oncol., Ill, 196-202... 

D. NADPH-Dependent Mixed Function Amine Oxidase. 153... 

The flavin-dependent mixed-function oxidases include amine N-oxidases and a variety of S-oxidases. They provide an alternative to cytochrome P450-dependent enzymes in the metabolism of xenobiotics. 

Eady, R. R., Jarman, T. R., and Large, P. J., 1971, Microhial oxidation of amines. Partial purification of a mixed function secondary amine oxidase system from Pseudomonas aminovo-rans that contains an enzymically active cytochrome P-420 type hemoprotein, Biochem. J. 125 4499459. 

The secondary amino group in (55) is then oxidized further to give the N-hydroxyl derivative (58), which is converted by a flavoprotein mixed-function amine oxidase into the nitrone derivative (59). Degradation of the nitrone metabolite, followed by oxidation yields 2-ni-troso-l-phenylpropane (60). 

Prough RA. 1973. The N-oxidation of alkylhydrazines catalyzed by the microsomal mixed-function amine oxidase. Arch Biochem Biophys 158 442-444. 

ESR investigations of microsomal drug oxidation have been reported. For example, the microsomal enzyme mixed function amine oxidase converts hindered hydroxyl-amines to the corresponding ESR-detectable nitroxides. From a comparison of rates of nitroxide and superoxide production, it has been concluded [177] that oxidation of the hydroxylamine is mediated solely by enzyme-generated superoxide radical. In addition, it appears that some oxidations mediated by cytochrome P-450 may occur, at least in part, by a one-electron mechanism. Oxidation of several dihydropyridine derivatives and some substituted hydrazines in the presence of spin traps has given spectra of spin-adducts consistent with radical production from the P-450 substrates [178]. Cumene hydroperoxide has been shown to support the P-450-catalyzed oxidation of aminopyrine to its radical cation [179]. 

We will discuss the carcinogenic properties of nitrosoamines in spite of the fact that it seems to be a problem particularly related to N-nitroso derivatives of secondary amines. In 1956, Magee and Barnes found that rats fed with N-nitrosodimethylamine developed hepatic tumors. Nitrosoamines cause alkylation of DNA, as suggested first by Druckrey et al. (1967) and Druckrey (1973). They postulated the pathway shown in (4-10), originally for 7V-nitrosodimethylamine, but likely to be valid for all dialkyl- and cycloalkylamines with at least one H-atom bonded to one of the C(a)-atoms. The nitrosoamine is metabolized by a cytochrome P450-dependent, so-called mixed-function oxidase. This enzyme catalyzes the hydroxylation of the C(a)-atom... 

Ziegler DM, Mitchell CH. Microsomal oxidase IV properties of a mixed-function amine oxidase isolated from pig liver microsomes. Arch Biochem Biophys 1972 150 116-125. 

The final stage in the biosynthesis of NA involves a second mixed function oxidase, dopamine- -hydroxylase. This enzyme has been extensively purified from the bovine adrenal medulla, and is a copper-containing protein of molecular weight 290,000. Ascorbic acid acts as the cofactor (XHj). Enzyme activity is stimulated by catalytic amounts of fumaric acid and by certain other dicarboxylic acids. The enzyme has a broad substrate specificity, and will catalyse the /7-hydroxylation of a large number of phenylethylamine derivatives, including a number of sympathomimetic amines (Table 8). 

Structural analogy with sphingosine prompts a predicted metabolic pathway for FB j. In Fig. 5 it is predicted that FB) may be (i) acylated by ceramide synthetase with or without removal of the side chains by carboxylesterase action and (ii) de-aminated by either monoamine oxidases or mixed function oxidases with or without esterase action to yield metabolites that would be expected to be inactive, since a free amino group appears to be required for activity. However, none of the metabolites predicted in Fig. 5 are likely to be highly active. 

---