Xanthine oxidase (XO or 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.
Reaction The following chemical reactions are catalyzed by xanthine oxidase:
hypoxanthine + H2O + O2 ⇌ xanthine + H2O2 xanthine + H2O + O2 ⇌ uric acid + H2O2 Xanthine oxidase can also act on certain other purines, pterins, and aldehydes. For example, it efficiently converts 1-methylxanthine (a metabolite of caffeine) to 1-methyluric acid, but has little activity on 3-methylxanthine. Under some circumstances it can produce superoxide ions: RH + H2O + 2 O2 ⇌ ROH + 2 O−2 + 2 H+.
Other reactions Because XO is a superoxide-producing enzyme, with general low specificity, it can be combined with other compounds and enzymes and create reactive oxidants, as well as oxidize other substrates. Bovine xanthine oxidase (from milk) was originally thought to have a binding site to reduce cytochrome c with, but it has been found that the mechanism to reduce this protein is through XO's superoxide anion byproduct, with competitive inhibition by carbonic anhydrase. Another reaction catalyzed by xanthine oxidase is the decomposition of S-nitrosothiols (RSNO), a class of reactive nitrogen species, to nitric oxide (NO), which reacts with a superoxide anion to form peroxynitrite under aerobic conditions. XO has also been found to produce the strong one-electron oxidant carbonate radical anion from oxidation with acetaldehyde in the presence of catalase and bicarbonate. It was suggested that the carbonate radical was likely produced in one of the enzyme's redox centers with a peroxymonocarbonate intermediate. Here is a diagram highlighting the pathways catalyzed by xanthine oxidase.
It is suggested that xanthine oxidoreductase, along with other enzymes, participates in the conversion of nitrate to nitrite in mammalian tissues.
Protein structure The protein is a homodimer and each subunit has a molecular weight of roughly 145 kDa. Each active site consists of a flavin molecule (bound as FAD), a Moco cofactor containing a molybdenum atom, and 2 [2Fe-2S] clusters containing 4 iron atoms. The Moco cofactors are the active sites of the enzyme, where oxidation occurs. The [2Fe-2S] clusters participate in the electron transfer reaction and the FAD facilitates the reduction of the electron acceptor.
Catalytic mechanism 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. Like other known molybdenum-containing oxidoreductases, the oxygen atom introduced to the substrate by XO originates from water rather than from dioxygen (O2).
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