Oxygenases with mixed functions

Hydroxylases (oxygenases with mixed functions). General equation ... 

These include the mitochondrial respiratory chain, key enzymes in fatty acid and amino acid oxidation, and the citric acid cycle. Reoxidation of the reduced flavin in oxygenases and mixed-function oxidases proceeds by way of formation of the flavin radical and flavin hydroperoxide, with the intermediate generation of superoxide and perhydroxyl radicals and hydrogen peroxide. Because of this, flavin oxidases make a significant contribution to the total oxidant stress of the body. 

Dihydroflavin can be oxidized by reaction with a substrate, NAD(P)+ or cytochromes in a variety of dehydrogenases, or can react with molecular oxygen in oxygenases and mixed-function oxidases. 

Laboratory trials during lampricide application (0.5-5.8 mg/L, 24-h exposure) with rainbow trout confirmed that field formulations of lampricides induce hepatic mixed function oxygenase enzymes activity. Mixed function oxygenase induction was associated with the 3-trifluoromethyl-4-nitrophenol formulation, and not the 2, 5-dichloroU -nitrosalicylanilidc (Bayer 73) component of the field application. Bioassays were successfully confirmed with HPLC [78]. 

Klingensmith JS, Mehendale HM. 1983a. Destruction of hepatic mixed-function oxygenase parameters by CC14 in rats following acute treatment with chlordecone, mirex, and phenobarbital. Life Sci 33(23) 2339-2348. 

Since the formation of the ethyleniminium ion is crucial for the cytotoxic activity of the nitrogen mustards, it is not surprising that stable ethylenimine derivatives have antitumor activity. Thiophospho-ramide or thiotepa is the best known compound of this type that has been used clinically. Both thiotepa and its primary metabolite, triethylenephos-phoramide (TEPA), to which it is rapidly converted by hepatic mixed-function oxygenases form crosslinks with DNA. It is mainly used as an intravesicu-lar agent in bladder cancer. Thiotepa produces little toxicity other than myelosuppression. 

The enzymes appear to be cytochrome Ph50 mixed-function oxygenases with electron transfer components similar to those found in liver (19,20). 

Metabolism of the cyclic diesters retrorsine (166), monocrotaline (169), and crispatine (171) by a variety of mammalian liver microsome preparations and by Peptococcus heliotrinreducans has been reported. Mattocks and co-workers have studied the metabolism of retrorsine by liver microsome preparations from several sources 167-169) and have demonstrated the conversion of this alkaloid to the corresponding iV-oxide 167 and a pyrrolic metabolite formulated as 168. The formation of 168 via 167 and dehydration is mitigated against by the observation that retrorsine TV-oxide (167) does not give rise to a pyrrolic metabolite on incubation with rat liver microsomes 167), even though the enzyme system responsible for the production of 168 from retrorsine has many of the properties of the mixed-function oxygenases capable of N-oxidation 167,174). The metabolites of retrorsine... 

The degradation of phenylalanine begins with its hydroxylation to tyrosine, a reaction catalyzed by phenylalanine hydroxylase. This enzyme is called a monooxygenase (or mixed-function oxygenase) because one atom ofO appears in... 

K. B. Sharpless, T. C. Flood, Oxotransition metal oxidants as mimics for the action of mixed-function oxygenases. "NIH shift" with chromyl reagents, /. Am. Chem. Soc. 93 (1971) 2316. 

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