Aldehyde oxidase and

Molybdenum. Molybdenum is a component of the metaHoen2ymes xanthine oxidase, aldehyde oxidase, and sulfite oxidase in mammals (130). Two other molybdenum metaHoen2ymes present in nitrifying bacteria have been characteri2ed nitrogenase and nitrate reductase (131). The molybdenum in the oxidases, is involved in redox reactions. The heme iron in sulfite oxidase also is involved in electron transfer (132). 

Beedham, C., Miceli, J. J. Obach, R. S. (2003). Ziprasidone metabolism, aldehyde oxidase, and clinical implications. J. Clin. Psychopharmacol, 23, 229-32. 

Hydroxylation of the benzylic methyl group of tolbutamide, the preferred site of oxidative attack by CYP2C9 (22), generates hydroxytolbutamide. Hydroxytolbutamide is rapidly oxidized by other enzymes, presumably aldehyde oxidase and/or alcohol dehydrogenase (ALD), to form the major isolated metabolite, the benzoic acid analog. 

Panoutsopoulos GI, Beedham C. Kinetics and specificity of guinea pig liver aldehyde oxidase and bovine milk xanthine oxidase towards substituted benzaldehydes. Acta Biochim Pol 2004 51(3) 649-663. 

Several compounds are inhibitors of CYP2A6-mediated nicotme metabolism m vitro, mcludmg methoxsalen (8-methoxypsoralen), tranylcypromine, tryptamine and coumarin (Le Gal et al. 2003 MacDougall et al. 2003 Nakajima et al. 1996 Zhang et al. 2001). Raloxifene is a potent inhibitor of aldehyde oxidase and it has been shown to inhibit the formation of cotinine from nicotme-A -iminium ion in human liver cytosol (Obach 2004). 

The potency of zebularine is about 10-fold lower than for the azacytosines [73]. Zebularine also inhibits cytidine deaminase [75] which is involved in nucleoside catabolism and deactivates also for example azacitidine and its desoxy analog [76]. Thus, it increases the concentrations of nucleoside triphosphates for incorporation into DNA, the efficacy of DNA methylation and ultimately the anticancer activity of for example azacitidine [77, 78[. Zebularine is metabolized by aldehyde oxidase and ithasbeen shovm that its activity can be increases if an inhibitor of that enzyme, for example raloxifene is given in combination [79]. One big question about all epigenetic drugs is the origin of the observed selectivity towards cancer cells. For zebularine, it has been shown that much less activation towards triphosphate metabolites that can be incorporated into DNA occurs in normal muscle tissue as compared to cancer tissue [80]. 

Cimetidine Cimetidine inhibits aldehyde oxidase and CYP3A4, the primary and secondary enzymes, respectively, responsible for zaleplon metabolism. Use an initial... 

Aldehydes and Ketones. Many metabolic routes are possible, including both oxidation and reduction. However, oxidations are more common. Aldehydes are very susceptible to oxidation, which is catalyzed by various enzymes including aldehyde oxidase and aldehyde dehydrogenase this oxidation yields a carboxylic acid. Ketones, on the other hand, tend to be stable to oxidation. Conversely, aldehydes are seldom metabolized by reduction. Ketones, however, frequently undergo reduction to a secondary alcohol this is particularly true for a,P-unsaturated ketones. 

This newest non-BZD hypnotic is a pyrazolopyrimidine derivative with a fuii agonist activity on centrai BZD receptors B2 type. It is an effective hypnotic for the short-term treatment of insomnia. Because of its very short half-life (almost an hour), it may be useful for patients experiencing difficulty falling asleep and in those who wake up at night and who have trouble falling back to sleep. Zaleplon is rapidly absorbed after oral administration and its mean, apparent elimination half-life is similar to that obtained after i.v. infusion. Zaleplon is extensively metabolized in the liver by aldehyde oxidase, and to a lesser extent by CYP3A4. This drug is excreted in the urine (156). 

Fe prosthetic groups.282 283 A group of aldehyde oxidases and xanthine dehydrogenases also contain molybdenum as well as iron (Chapter 16). In every case the metal ions are bound independently of the flavin.2833... 

Other enzymes in the soluble fraction of liver that oxidize aldehydes are aldehyde oxidase and xanthine oxidase, both flavoproteins that contain molybdenum however, their primary role seems to be the oxidation of endogenous aldehydes formed as a result of deamination reactions. 

Zaleplon is primarily metabolized by aldehyde oxidase and use with inhibitors of this enzyme, such as cimetidine, may result in increased plasma concentrations of zaleplon. Zaleplon is also partly metabolized by the cytochrome P450 isoenzyme CYP3A4 and, consequently, caution is advised when zaleplon is given with drugs that are substrates for, or potent inhibitors of, this isoenzyme. Cimetidine is also an inhibitor of CYP3A4 and thus inhibits both the primary and secondary metabolic pathways of zaleplon. Use with rifampicin or other potent enzyme-inducing drugs may accelerate the metabolism of zaleplon and reduce its plasma concentrations [40]. 

Zaleplon is rapidly and almost completely absorbed following oral administration of a 10 mg dose. The compound undergoes significant first-pass hepatic metabolism after absorption. As a result, its bioavailability amounts to only 30 %. The compound attains maximum plasma concentration in approximately 1 h and has a terminal ti/2 of 1.0 h. Zaleplon is primarily metabolized by aldehyde oxidase, and all of its metabolites are pharmacologically inactive [28, 29],... 

Tasayco M. L. and Prestwich G. D. (1990c) Aldehyde oxidases and dehydrogenases in antennae of 5 moth species. Insect Biochem. 20, 691-700. 

Studies with various subcellular fractions are useful to ascertain which enzyme systems are involved in the metabolism of a chug candidate. In the absence of added cofactors, oxidative reactions such as oxidative deamination that are supported by mitochondria or by Ever microsomes contaminated with mitochondria membranes (as is the case with microsomes prepared from frozen liver samples) are likely catalyzed by monoamine oxidase (MAO), whereas oxidative reactions supported by cytosol are likely catalyzed by aldehyde oxidase and/or xanthine oxidase (a possible role for these enzymes in the metabolism of... 

Evidence Concerning the Molybdenum Site. Despite considerable debate, there is at present a good deal of agreement as to the overall mode of functioning of xanthine oxidase (20, 65-70). Furthermore, the EPR spectroscopic properties indicate that the molybdenum sites in aldehyde oxidase and (to a somewhat lesser extent) sulfite oxidase are very similar in nature to that in xanthine oxidase. 

The other molybdenum enzymes each contain duplicate prosthetic groups and paired subunits in addition to two molybdenum atoms. Many of the experiments performed for xanthine oxidase have also been carried out with aldehyde oxidase and sulfite oxidase, and there is no evidence for chemical Mo-Mo coupling in these enzymes. Thus, in oxidases, the evidence for mononuclear molybdenum sites appears strong, and in view of the duplicate subunits and composition found, it is reasonable to assume a similar situation in reductases as well. However, at present, insufficient information bars a full generalization. 

In addition to liver aldehyde dehydrogenase, a number of other enzymes present in the soluble fraction of liver homogenates will oxidize aldehydes and certain N-heterocyclic compounds. Among these are aldehyde oxidase and xanthine oxidase (see below), both flavoprotein enzymes containing molybdenum. These enzymes catalyze the oxidation of aldehydes formed by the deamination of endogenous amines by amine oxidases. 

ABA-deficient mutants663 have confirmed that ABA-aldehyde is the immediate precursor of ABA. Arabidopsis has four isozyme genes of aldehyde oxidase, and an AA03 protein, which is one of the isozymes catalyzing the conversion reaction of ABA-aldehyde to ABA.664 AA03 could be the ABA-aldehyde oxidase gene. 

In addition to hydroxylating xanthine and a wide range of purines, pteridines and similar compounds, xanthine oxidase is able to oxidize aromatic and aliphatic aldehydes to the corresponding carboxylic acids. Clearly then, there is a close functional as well as structural relationship between xanthine oxidase and the eukaryotic aldehyde oxidases and prokaryotic oxidoreductases. With xanthine oxidase, the pH dependence of the kinetic parameter (obtained from the substrate concentration dependence... 

Five proteins containing molybdenum are known nitrate reductase, nit-rogenase, xanthine oxidase, aldehyde oxidase and sulphite oxidase. They also contain iron, and the first four are best classified as multi-enzyme systems. Early studies on xanthine oxidase used a number of important ESR techniques, particularly rapid freeze kinetic methods and isotopic substitution in metalloproteins. This work has been reviewed [38, 39], Nitrogenase is the subject of considerable recent interest since it contains detectable iron-sulphur centres but as there is some disagreement at present concerning the interpretations of the results readers are referred to the original literature [40-42]. 

The bioconversion of alcohols to aldehydes and ketones is catalyzed by soluble alcohol dehydrogenases present in the liver and other tissues. NAD is required os a coenzyme, although NADP also may serve as a coenzyme. The reaction catalyzed by alcohol dehydrogenase is reversible but often proceeds to the right because the aldehyde formed is fuithcr oxidized to the acid. Several aldehyde dehydrogenases, including aldehyde oxidase and xanthine oxidase, carry out the oxidation of aldehydes to their corresponding acids." - ... 

Ohkubo, M., and Fujimura, S. Rat liver N-methyl-nicotinamide oxidase I and II Substrate non-specific enzyme "aldehyde oxidase" and specific enzyme. Biochem Int 4 353-358, 1982. 

Similarly, neither iron nor copper can substitute for molybdenum once removed from metal-free xanthine or aldehyde oxidase, and up to 5000 times the number of molecules of molybdenum removed are necessary for reactivation of one molecule of apoenzyme (Mahler and Green, 1954). 

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