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Class of enzymes

Xanthine oxidase (XO, sometimes XAO) is a form of xanthine oxidoreductase, a type of enzyme that generates reactive oxygen species. These enzymes catalyze the oxidation of hypoxanthine to xanthine and can further catalyze the oxidation of xanthine to uric acid. These enzymes play an important role in the catabolism of purines in some species, including humans. Xanthine oxidase is defined as an enzyme activity (EC 1.17.3.2). The same protein, which in humans has the HGNC approved gene symbol XDH, can also have xanthine dehydrogenase activity (EC 1.17.1.4). Most of the protein in the liver exists in a form with xanthine dehydrogenase activity, but it can be converted to xanthine oxidase by reversible sulfhydryl oxidation or by irreversible proteolytic modification.

The protein is large, having a molecular weight of 270 kDa, and has two flavin molecules (bound as FAD), 2 molybdenum atoms, and 8 iron atoms bound per enzymatic unit. The molybdenum atoms are contained as molybdopterin cofactors and are the active sites of the enzyme. The iron atoms are part of [2Fe 2S] ferredoxin iron sulfur clusters and participate in electron transfer reactions.

The active site of XO is composed of a molybdopterin unit with the molybdenum atom also coordinated by terminal oxygen (oxo), sulfur atoms and a terminal hydroxide. In the reaction with xanthine to form uric acid, the S=MoVIO H group ionizes and the resulting MoVI O attacks carbon concomitant with transfer of H to Mo=S. The resulting HS MoIV O C center then undergoes 2e oxidation with hydrolysis of the MoVI O C group, giving back S=MoVI OH, together with xanthine. During severe liver damage, xanthine oxidase is released into the blood, so a blood assay for XO is a way to determine if liver damage has happened. Because xanthine oxidase is a metabolic pathway for uric acid formation, the xanthine oxidase inhibitor allopurinol is used in the treatment of gout. Since xanthine oxidase is involved in the metabolism of 6 mercaptopurine, caution should be taken before administering allopurinol and 6 mercaptopurine, or its prodrug azathioprine, in conjunction. Xanthinuria is a rare genetic disorder where the lack of xanthine oxidase leads to high concentration of xanthine in blood and can cause health problems such as renal failure. There is no specific treatment, affected people are advised by doctors to avoid foods high in purine and to maintain a high fluid intake. Type I xanthinuria has been traced directly to mutations of the XDH gene which mediates xanthine oxidase activity. Type II xanthinuria may result from a failure of the mechanism which inserts sulfur into the active sites of xanthine oxidase and aldehyde oxidase, a related enzyme with some overlapping activities (such as conversion of allopurinol to oxypurinol). Inhibition of xanthine oxidase has been proposed as a mechanism for improving cardiovascular health. A study found that patients with chronic obstructive pulmonary disease (COPD) had a decrease in oxidative stress, including glutathione oxidation and lipid peroxidation, when xanthine oxidase was inhibited using allopurinol. Oxidative stress can be caused by hydroxyl free radicals and hydrogen peroxide, both of which are byproducts of XO activity. Increased concentration of serum uric acid has been under research as an indicator for cardiovascular health factors, and has been used to strongly predict mortality, heart transplant, and more in patients. States of high cell turnover and alcohol ingestion are some of the most prominent cases of high serum uric acid concentrations. Both xanthine oxidase and xanthine oxidoreductase are also present in corneal epithelium and endothelium and may be involved in oxidative eye injury.

Inhibitors of XO include allopurinol, oxypurinol, and phytic acid. It has also been found to be inhibited by flavonoids, including those found in Bougainvillea spectabilis (Nyctaginaceae) leaves (with an IC50 of 7.23 μM), typically used in folk medicine.