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  • Xanthine oxidoreductase (XOR) catalyzes the final reactions of the purine catabolic pathway, oxidizing hypoxanthine to xanthine and xanthine to uric acid. Inherited deficiency of the enzyme results in xanthinuria (MIM 278300), which is usually clinically mild or asymptomatic. Precipitation of xanthine in the urinary tract or muscle may give rise to the most common symptoms, urolithiasis (with secondary renal damage) and muscle pain. Biochemically the disease is characterized by low uric acid and elevated xanthine in plasma and urine. Xanthinuria is an autosomal recessive disease.

  • In addition to hypoxanthine and xanthine, XOR oxidizes adenine, 6-mercaptopurine, and allopurinol; a number of pyrimidines, aldehydes, and pterins are also substrates. Under physiological conditions, XOR functions mainly as a dehydrogenase, with NAD+ as the cosubstrate, but it can be converted into an oxidase, which utilizes molecular oxygen as the cosubstrate and produces hydrogen peroxide and superoxide. The enzyme may also form nitric oxide by reducing nitrite or by cleaving nitrosothiols. The Km values of both the dehydrogenase and the oxidase for the purine substrates are in the range of 10−6–10−5 M.

  • Reversible conversion of xanthine dehydrogenase into oxidase occurs by sulfhydryl group oxidation, which results in loss of the NAD+ binding site. Irreversible proteolytic conversion into oxidase occurs upon enzyme purification, tissue ischemia, or treatment with proteolytic enzymes. In cell and tissue extracts, 7–35 percent of total enzyme activity is accounted for by the oxidase. Inactive enzyme forms include desulfo-XOR and demolybdo-XOR.

  • The human XOR gene is located on chromosome 2p22, spans at least 60 kb, and consists of 36 exons and 35 introns. The cDNA for human xanthine dehydrogenase corresponds to a polypeptide of 1333 amino acids, with a predicted molecular weight of ∼146 kDa. Purified human XOR is a dimer of two identical subunits of ∼150 kDa. Each subunit consists of three domains, cleavable by proteolysis but remaining associated under nondenaturing conditions. The N-terminal 20-kDa domain contains two nonidentical Fe-S centers, the middle 40-kDa domain contains an FAD center, and the C-terminal 85-kDa domain contains molybdenum bound to a cofactor. Catalysis is initiated by the transfer of two electrons to the Mo(VI) atom, followed by intramolecular electron transfer to the Fe-S centers and finally to FAD, which is then oxidized by either NAD+ or oxygen. Allopurinol inhibits the enzyme after being converted into oxypurinol, which binds tightly to the molybdenum center.

  • Enzyme activity, immunoreactive protein, and mRNA of XOR are abundantly expressed in human proximal small intestine and liver; low activity is inconsistently present in kidney and lung. Immunohistochemistry shows expression in intestinal epithelial cells and hepatocytes, faintly in other organs' capillary endothelial cells. Resting mammary epithelium contains enzyme protein, which increases during lactation. No activity, protein, or mRNA can be detected in human myocardium or brain. Basal expression is increased during hypoxia by posttranslational mechanisms. Hyperoxia suppresses enzyme activity by inactivation of the enzyme protein and by inhibition of transcription. Several cytokines (e.g., γ-interferon) activate ...

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