Molybdenum Hydroxylases AOs XOsXDHs

This class includes three groups: aldehyde oxidases (AOs; EC number 1.2.3.1), xanthine oxidases (XOs; EC number 1.2.3.2), and xanthine dehydrogenases (XDHs; EC number 1.17.1.4). XDHs are the dehydrogenase forms of XOs. AOs do not have a dehydro-genase form.

Subcellular location: Cytosol.

Organ distribution: AOs are present in highest concentration in the liver, followed by the lung, kidney, and small intestine and are not present in milk or in the brain.

XOs play a minor role in metabolizing drugs. They are present at highest concentrations in the liver, followed by the lung, kidney, and small intestine. They are found in milk and lactating glands. Very little to no XOs are found in the brain.

The source of the oxygen atom is from water and not O2.

Active site: Contains molybdenum (Mo), Fe-S clusters, and FAD.

AO Reactions:

1. Oxidation of aliphatic and aromatic aldehydes to carboxylic acids (as the name refers, but this is a minor role it plays in humans, mostly this reaction is catalyzed by aldehyde dehydro-genases (ALDHs)).

2. Oxidation of electron-deficient sp2-hybridized carbon next to nitrogen such as azaheterocyclic compounds and iminium ions. it was recently shown that this reaction is well predicted by determining the energetics for the intermediate formed (Torres et al. 2007).

3. Oxazole and thiazole reduction.

4. Reduction of N-oxides to amines (for example, brucine N-oxide to brucine).

5. Reduction of hydroxamic acids to amides (for example, nicoti-nohydroxamic acid to nicotinamide).

6. Reduction of nitro compounds to N-oxides (for example, conversion of benznidazole to benznidazole hydroxylamine).

7. Reduction of S-oxides to thiols (for example, sulindac sulfoxide to sulindac sulfide).

8. Epoxides to alkenes (e.g., benzo[a]pyrene-oxide to benzo[a] pyrene) (Fig. 2.5).

Figure 2.5. Various reactions catalyzed by molybdenum hydroxylases (AOs).

SGX523 (a cMet inhibitor) is metabolized by AOs to a 2-quino-linone metabolite that can result in crystal deposits in renal tubules, leading to renal toxicity (Diamond et al. 2010). This metabolite is formed in humans and monkeys, but not in dogs because dogs do not have any active AOs.

Isoforms: Humans have only one AO isoform, which is relatively labile. There are four AO isoforms in rodents with generally low activity, and there are no AOs in dogs. In general, AOs have broad substrate selectivity compared to XOs. AOs have more pronounced species differences than do XOs. Female rodents generally have greater AO functional activity than do male rodents. The active site of AOs in humans is the largest among the species and, therefore, accommodates more diverse substrates.

AO substrates: Phthalazine and allopurinol.

AO inhibitors: Menadione, isovanillin, raloxifene, perphenazine, thioridazine, and allopurinol (higher concentrations). Typically, substrates of AOs at higher concentrations are inhibitors.

XO substrate: Allopurinol.

XO inhibitors: Folic acid, allopurinol, and alloxanthine.

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