Abstract
Xanthine oxidoreductase (XOR) catalyzes the conversion of hypoxanthine to xanthine and xanthine to uric acid with concomitant reduction of either NAD+ or O2. The enzyme is a target of drugs to treat hyperuricemia, gout and reactive oxygen-related diseases. Human diseases associated with genetically determined dysfunction of XOR are termed xanthinuria, because of the excretion of xanthine in urine. Xanthinuria is classified into two subtypes, type I and type II. Type I xanthinuria involves XOR deficiency due to genetic defect of XOR, whereas type II xanthinuria involves dual deficiency of XOR and aldehyde oxidase (AO, a molybdoflavo enzyme similar to XOR) due to genetic defect in the molybdenum cofactor sulfurase. Molybdenum cofactor deficiency is associated with triple deficiency of XOR, AO and sulfite oxidase, due to defective synthesis of molybdopterin, which is a precursor of molybdenum cofactor for all three enzymes. The present review focuses on mutation or chemical modification studies of mammalian XOR, as well as on XOR mutations identified in humans, aimed at understanding the reaction mechanism of XOR and the relevance of mutated XORs as models to estimate the possible side effects of clinical application of XOR inhibitors.
Highlights
Xanthine oxidoreductase (XOR) catalyzes two hydroxylation steps in the metabolic pathway of purine degradation, i.e., hypoxanthine to xanthine and xanthine to uric acid, utilizing either NAD+ orO2 [1,2,3] (Figure 1)
The present review focuses mainly on mutational studies of XOR and mutations associated with hereditary dysfunction of XOR in humans, since these are useful for understanding the enzyme reaction mechanism and as models to estimate the possible side effects of using XOR
Human diseases associated with genetic dysfunction of XOR are termed xanthinuria, because xanthine is excreted in the urine [33]
Summary
Xanthine oxidoreductase (XOR) catalyzes two hydroxylation steps in the metabolic pathway of purine degradation, i.e., hypoxanthine to xanthine and xanthine to uric acid, utilizing either NAD+ or. As XOR inhibitors significantly lower uric acid production and concentration in the blood, they can be used to treat gout. Spectroscopic and structural-biological analyses of the inhibition mechanism, it has been shown that these recently developed inhibitors bind tightly to both the oxidized and reduced forms of XOR in a highly structure-specific manner [15], whereas allopurinol, a substrate analogue, binds covalently to the reduced molybdenum atom (MoIV) after having been converted to the hydroxylated product (oxipurinol: alloxanthine) [20], mimicking the reaction intermediate formed during the hydroxylation reaction with xanthine as a substrate [21]. Potent inhibition seems to be essential to lower the uric acid level in blood or tissue, since XOR is a house-keeping enzyme that exists abundantly in various organs [10]. The present review focuses mainly on mutational studies of XOR and mutations associated with hereditary dysfunction of XOR in humans, since these are useful for understanding the enzyme reaction mechanism and as models to estimate the possible side effects of using XOR inhibitors as drugs
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