Aldehyde oxidase heterocycles

Already in 1946, Knox (46JBC699) presented evidence for the ability of a crude preparation of rabbit liver aldehyde oxidase to catalyze oxidation of diverse quaternary aromatic heterocyclic compounds. Later, it was demonstrated that mammalian liver contains an enzyme system that can oxidize N-methylnicotinamide 230 to both the pyridones 231 and 232 (64JBC2027 66BBA556 67JBC1271 67JBC1274). 

Aldehyde oxidase, a non-microsomal enzyme discussed in more detail below, may also be involved in the oxidation of quinoline to give 2-hydroxyquinoline (Fig. 4.14). The heterocyclic phthalazine ring in the drug hydralazine is oxidized by the microsomal enzymes to phthalazinone. The mechanism, which may involve nitrogen oxidation, is possibly involved in the toxicity of this drug (see chap. 7). Again, other enzymes may also be involved (Fig. 4.15). 

Purine oxidation. The oxidation of purines and purine derivatives is catalyzed by xanthine oxidase. For example, the enzyme oxidizes hypoxanthine to xanthine and thence uric acid (Fig. 4.34). Xanthine oxidase also catalyzes the oxidation of foreign compounds, such as the nitrogen heterocycle phthalazine (Fig. 4.35). This compound is also a substrate for aldehyde oxidase, giving the same product. 

In addition to these classical aromatic ring hydroxylations, many nitrogen heterocycles are substrates for molybdenum-containing enzymes, such as xanthine oxidase and aldehyde oxidase, which are present in the hepatic cytosolic fractions from various animal species. The molybdenum hydroxylases (B-75MI10902) catalyze the oxidation of electron-deficient carbons in aromatic nitrogen heterocycles. The reactions catalyzed by these enzymes are generally represented by equations (2) and (3). 

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. 

There are a number of molybdenum-containing enzymes, but those that are important in carbon oxidation of xenobiotics are aldehyde oxidase (AO) and xanthine oxidase (XO), also referred to as molybdenum hydroxylases (Figure 10.7). Both enzymes catalyze the oxidation of a wide range of aldehydes and N-heterocycles. The name aldehyde oxidase is somewhat misleading, however, because oxidation of heteroaromatics is more significant. The differences in substrate specificities between... 

Several important mammalian enzymes, such as sulfite oxidase, xanthine dehydrogenase, and aldehyde oxidase, require molybdenum as a cofactor. This organic component is a molybdopterin complex.Sulfite oxidase is probably the most important enzyme in relation to human health. This enzyme catalyzes the last step in the degradation of sulfur amino acids, oxidizing sulfite to sulfate and transferring electrons to cytochrome c. Xanthine dehydrogenase and aldehyde oxidase hydroxylate a number of heterocyclic substances, such as purines, pteridines, and others. ... 

FIGURE 17.6 A reaction mechanism for the aldehyde oxidase group of molybdenum hydroxylases. As with hydroxylation of heterocycles, the conversion of aldehydes to the corresponding carboxylic acids has been proposed to proceed via bases-assisted nucleophilic attack of the Mo—OH on the substrate carbonyl, with concomitant hydride transfer to the Mo=S. (From Hille, 2005. Copyright 2005 with permission from Elsevier.)... 

In agreement with what has been observed in animals, the level of aldehyde oxidase activity present in human liver is also markedly dependent on the substrate employed, the analytical method used to evaluate the substrate, and most importantly, the intrinsic activity of the preparation (Beedham et al. 1992). For N-1-methylnicotinamide oxidase activity, the rank order was cynomolgus monkey > rat > beagle dog > human liver (Rodrigues 1994). The relative levels of aldehyde oxidase activity may help determine the relative extent of lactim formation from N-heterocyclic compounds such as N-1-methylnicotinamide. Of course, formation of lactim metabolites from iminium ions can also be coordinately regulated by other enzyme activities including cytochromes P-450. Thus, formation of... 

Other enzymes may also be involved in the oxidation of aldehydes, particularly aldehyde oxidase and xanthine oxidase, which belong to the molybdenum hydroxylases. These enzymes are primarily cytosolic, although microsomal aldehyde oxidase activity has been detected. They are flavoproteins, containing FAD and also molybdenum, and the oxygen incorporated is derived from water rather than molecular oxygen. Aldehyde oxidase and xanthine oxidase in fact oxidize a wide variety of substrates, both aldehydes and nitrogen containing heterocycles such as caffeine and purines (see below). Aldehyde... 

Xanthine oxidoreductase and aldehyde oxidase are the principal enzymes involved in the oxidation of exocydic DNA adducts. Their role in purine catabolism and in the oxidation of nitrogen-rich heterocycles is well documented [143-145]. 

Aldehyde oxidase (EC 1.2.3.1) and xanthine oxidase (EC 1.2.3.2) are molybdenum-containing enzymes which catalyse the oxidation of many aldehydes and nitrogen heterocycles. In addition, they have also been shown... 

Simple unsubstituted monocycles such as pyridine, pyrazine, pyrimidine, pyridazine and pyrrole show little or negligible binding to either enzyme [3, 10, 173], However, we have shown that fusion or substitution of a phenyl group significantly increases the affinity of the compounds towards aldehyde oxidase, and in some cases the heterocycles are substrates for xanthine oxidase (Table 3.6) [50, 173]. Furthermore, studies with compounds containing a... 

Despite the charge on A-heterocyclic cations, lipophilicity is also a determining factor in the binding of such compounds to aldehyde oxidase thus, A-methylpyridinium does not serve as a substrate for aldehyde oxidase but only functions as a poor competitive inhibitor [159], whereas more lipophilic analogues are excellent substrates of the enzyme (Table 3.7) [57]. However,... 

S.M. Taylor, Specificity of aldehyde oxidase towards JV-heterocyclic cations, Ph.D. Thesis, Bradford University (1984). 

Not all oxidations of alkaloids can be ascribed to microsomal P-450 systems. Mammalian liver contains a flavoprotein oxidase, first discovered in rabit liver and called quinine oxidase . It is also an aldehyde oxidase, and its mechanism of action on heterocyclic nitrogen compounds probably involves addition of hydroxide ion to a suitable ring position, followed by dehydrogenation. Thus, the introduced oxygen atom comes from water rather than from molecular oxygen, in contrast to the P-450 oxygenases. [2]. 

Thus, the Mo center is involved in the oxidation of the substrate. In the mechanism, the source of the oxygen atom inserted into the substrate is H2O instead of O2 (as with P450 and FMO). The list of substrates includes some endogenous and xenobiotic aldehydes, and various heterocycles, including purines, pyridines, pyrimidines, pteridines, and others. Xanthine is a substrate for xanthine dehydrogenase but not aldehyde oxidase purines are substrates for both. 

Mammalian aldehyde oxidases (AOs) catalyze the oxidation of aldehydes to carboxylic acids and play important roles in the metabolism of N-heterocyclic compounds, the reduction of nitro-aromatic compounds and the... 

A comparison of the substrate specificities of bovine milk xanthine oxidase and rabbit liver aldehyde oxidase revealed both similarities and differences [10]. Both enzymes exhibited a preference for heterocycles which contain a condensed-pyrimidine ring system (Figure 3). Of the unsubstituted ring systems studied,... 

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