Editing Xanthine oxidase

{{Short description|Class of enzymes}}
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{{Use dmy dates|date=April 2017}}
{{Infobox enzyme
| Name       = xanthine oxidase/dehydrogenase
| EC_number  = 1.17.3.2
| CAS_number = 9002-17-9
| GO_code    = 0004855
| image      = XanthineOxidase-1FIQ.png
| width      =
| caption    = Crystallographic structure (monomer) of bovine xanthine oxidase.<ref name="pmid11005854">{{PDB|1FIQ}}; {{cite journal | vauthors = Enroth C, Eger BT, Okamoto K, Nishino T, Nishino T, Pai EF | title = Crystal structures of bovine milk xanthine dehydrogenase and xanthine oxidase: structure-based mechanism of conversion | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 97 | issue = 20 | pages = 10723–8 | date = September 2000 | pmid = 11005854 | pmc = 27090 | doi = 10.1073/pnas.97.20.10723 | bibcode = 2000PNAS...9710723E | doi-access = free }}</ref><br />The bounded FAD (red), FeS-cluster (orange), the molybdopterin cofactor with molybdenum (yellow) and salicylate (blue) are indicated.
}}
{{Infobox protein
| Name = xanthine oxidase/dehydrogenase
| caption = 
| image =
| width =
| HGNCid = 12805
| Symbol = [[Xanthine dehydrogenase|XDH]]
| AltSymbols =
| EntrezGene = 7498
| OMIM = 607633
| RefSeq = NM_000379
| UniProt = P47989
| PDB = 1FIQ
| ECnumber =  1.17.3.2
| Chromosome = 2
| Arm = p
| Band = 23.1
| LocusSupplementaryData =
}}
'''Xanthine oxidase''' ('''XO''' or '''XAO''') is a form of xanthine oxidoreductase, a type of [[enzyme]] that generates [[reactive oxygen species]].<ref>{{cite journal | vauthors = Ardan T, Kovaceva J, Cejková J | title = Comparative histochemical and immunohistochemical study on xanthine oxidoreductase/xanthine oxidase in mammalian corneal epithelium | journal = Acta Histochemica | volume = 106 | issue = 1 | pages = 69–75 | date = February 2004 | pmid = 15032331 | doi = 10.1016/j.acthis.2003.08.001 }}</ref> 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.<ref name=Hille>{{cite journal | vauthors = Hille R, Hall J, Basu P | title = The Mononuclear Molybdenum Enzymes | journal = Chemical Reviews | volume = 114 | issue = 7 | pages = 3963–4038 | date = April 2014 | pmid = 24467397 | pmc = 4080432 | doi = 10.1021/cr400443z }}</ref>

Xanthine oxidase is defined as an ''enzyme activity'' (EC 1.17.3.2).<ref>{{cite web|url=http://www.genome.jp/dbget-bin/www_bget?ec:1.17.3.2|title=KEGG record for EC 1.17.3.2|website=Genome.jp|access-date=23 December 2017}}</ref>  The same protein, which in humans has the [[HGNC]] approved gene symbol ''XDH'', can also have [[xanthine dehydrogenase]] activity (EC 1.17.1.4).<ref name="KEGG record for EC 1.17.1.4">{{cite web|url=http://www.genome.jp/dbget-bin/www_bget?ec:1.17.1.4|title=KEGG record for EC 1.17.1.4|website=Genome.jp|access-date=23 December 2017}}</ref>  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.<ref name="entrez">{{EntrezGene|7498}} "XDH xanthine dehydrogenase"</ref><ref>{{OMIM|607633|Xanthine dehydrogenase; XDH}}</ref>

==Reaction==
The following chemical reactions are catalyzed by xanthine oxidase:
* [[hypoxanthine]] + H<sub>2</sub>O + O<sub>2</sub> {{eqm}} [[xanthine]] + H<sub>2</sub>O<sub>2</sub>
* xanthine + H<sub>2</sub>O + O<sub>2</sub> {{eqm}} [[uric acid]] + H<sub>2</sub>O<sub>2</sub>
* Xanthine oxidase can also act on certain other [[purine]]s, [[pterin]]s, and [[aldehyde]]s.  For example, it efficiently converts [[1-methylxanthine]] (a metabolite of [[caffeine]]) to 1-methyluric acid, but has little activity on 3-methylxanthine.<ref>{{cite journal | vauthors = Birkett DJ, Miners JO, Valente L, Lillywhite KJ, Day RO | title = 1-Methylxanthine derived from caffeine as a pharmacodynamic probe of oxypurinol effect | journal = British Journal of Clinical Pharmacology | volume = 43 | issue = 2 | pages = 197–200 | date = February 1997 | pmid = 9131954 | pmc = 2042732 | doi = 10.1046/j.1365-2125.1997.53711.x }}</ref>
* Under some circumstances it can produce [[superoxide]] ions: RH + H<sub>2</sub>O + 2 O<sub>2</sub> {{eqm}} ROH + 2 {{chem|O|2|−}} + 2 H<sup>+</sup>.<ref name="KEGG record for EC 1.17.1.4"/>

<gallery>
 Image:Hypoxanthin.svg|[[hypoxanthine]] (one oxygen atom)
 Image:Xanthin - Xanthine.svg|[[xanthine]] (two oxygens)
 Image:Harnsäure Ketoform.svg|[[uric acid]] (three oxygens)
</gallery>

=== Other reactions ===
Because XO is a superoxide-producing enzyme, with general low specificity,<ref name="MG Bonini et al">{{cite journal | vauthors = Bonini MG, Miyamoto S, Di Mascio P, Augusto O | title = Production of the carbonate radical anion during xanthine oxidase turnover in the presence of bicarbonate | journal = The Journal of Biological Chemistry | volume = 279 | issue = 50 | pages = 51836–43 | date = December 2004 | pmid = 15448145 | doi = 10.1074/jbc.M406929200 | s2cid = 20161424 | doi-access = free }}</ref> 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]].<ref name="JM McCord & I. Fridovich">{{cite journal |last1=McCord |first1=J M |last2=Fridovich |first2=I |title=The Reduction of Cytochrome c by Milk Xanthine Oxidase |journal=Journal of Biological Chemistry |date=November 1968 |volume=243 |issue=21 |pages=5753–5760 |doi=10.1016/S0021-9258(18)91929-0 |pmid=4972775 |doi-access=free }}</ref>

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.<ref name="M Trujillo">{{cite journal | vauthors = Trujillo M, Alvarez MN, Peluffo G, Freeman BA, Radi R | title = Xanthine oxidase-mediated decomposition of S-nitrosothiols | journal = The Journal of Biological Chemistry | volume = 273 | issue = 14 | pages = 7828–34 | date = April 1998 | pmid = 9525875 | doi = 10.1074/jbc.273.14.7828 | s2cid = 10221482 | doi-access = free }}</ref>

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.<ref name="MG Bonini et al" />

Here is a diagram highlighting the pathways catalyzed by xanthine oxidase.

[[File:Xanthine oxidase pathways.jpg|frameless|A diagram illustrating many of 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.<ref>{{Cite journal |pmid = 18516050|year = 2008|last1 = Jansson|first1 = E. A.|last2 = Huang|first2 = L.|last3 = Malkey|first3 = R.|last4 = Govoni|first4 = M.|last5 = Nihlén|first5 = C.|last6 = Olsson|first6 = A.|last7 = Stensdotter|first7 = M.|last8 = Petersson|first8 = J.|last9 = Holm|first9 = L.|last10 = Weitzberg|first10 = E.|last11 = Lundberg|first11 = J. O.|title = A mammalian functional nitrate reductase that regulates nitrite and nitric oxide homeostasis|journal = Nature Chemical Biology|volume = 4|issue = 7|pages = 411–7|doi = 10.1038/nchembio.92}}</ref>

==Protein structure==
The protein is large, having a [[molecular weight]] of 270&nbsp;kDa, and has two [[Flavin group|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 cluster]]s and participate in electron transfer reactions.{{citation needed|date=July 2024}}

==Catalytic mechanism==
The active site of XO is composed of a molybdopterin unit with the molybdenum atom also coordinated by terminal oxygen ([[oxo ligand|oxo]]), sulfur atoms and a terminal [[hydroxide]]. In the reaction with xanthine to form uric acid, the S=Mo<sup>VI</sup>O-H group ionizes and the resulting MoVI-O<sup>−</sup> attacks carbon concomitant with transfer of H<sup>−</sup> to Mo=S.  The resulting HS-Mo<sup>IV</sup>-O-C center then undergoes 2e oxidation with hydrolysis of the MoVI-O-C group, giving back S=Mo<sup>VI</sup>-OH, together with  xanthine.<ref name=Hille/>  Like other known molybdenum-containing oxidoreductases, the oxygen atom introduced to the [[Substrate (biochemistry)|substrate]] by XO originates from water rather than from [[dioxygen]] (O<sub>2</sub>).{{citation needed|date=July 2024}}

==Clinical significance==
Xanthine oxidase is a [[superoxide]]-producing enzyme found normally in [[Serum (blood)|serum]] and the lungs, and its activity is increased during [[Influenza A virus|influenza A]] infection.<ref name="pmid1547201">{{cite journal |last1=Hemilä |first1=Harri |title=Vitamin C and the common cold |journal=British Journal of Nutrition |date=January 1992 |volume=67 |issue=1 |pages=3–16 |doi=10.1079/bjn19920004 |pmid=1547201 }}</ref>

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.<ref name="pmid11316169">{{cite journal | vauthors = Battelli MG, Musiani S, Valgimigli M, Gramantieri L, Tomassoni F, Bolondi L, Stirpe F | title = Serum xanthine oxidase in human liver disease | journal = The American Journal of Gastroenterology | volume = 96 | issue = 4 | pages = 1194–9 | date = April 2001 | doi = 10.1111/j.1572-0241.2001.03700.x | pmid = 11316169 | s2cid = 36068630 }}</ref>

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]]).<ref>{{OMIM|603592|Xanthinuria, Type II; XAN2}}</ref>

Inhibition of xanthine oxidase has been proposed as a mechanism for improving cardiovascular health.<ref name="pmid21894646">{{cite journal | vauthors = Dawson J, Walters M | title = Uric acid and xanthine oxidase: future therapeutic targets in the prevention of cardiovascular disease? | journal = British Journal of Clinical Pharmacology | volume = 62 | issue = 6 | pages = 633–44 | date = December 2006 | pmid = 21894646 | pmc = 1885190 | doi = 10.1111/j.1365-2125.2006.02785.x }}</ref> 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.<ref name="LM Heunks et al.">{{cite journal | vauthors = Heunks LM, Viña J, van Herwaarden CL, Folgering HT, Gimeno A, Dekhuijzen PN | title = Xanthine oxidase is involved in exercise-induced oxidative stress in chronic obstructive pulmonary disease | journal = The American Journal of Physiology | volume = 277 | issue = 6 Pt 2 | pages = R1697–704 | date = December 1999 | pmid = 10600916 | doi = 10.1152/ajpregu.1999.277.6.R1697 | s2cid = 4518363 }}</ref> Oxidative stress can be caused by hydroxyl free radicals and hydrogen peroxide, both of which are byproducts of XO activity.<ref name="P. Higgins et al.">{{cite journal | vauthors = Higgins P, Dawson J, Walters M | title = The potential for xanthine oxidase inhibition in the prevention and treatment of cardiovascular and cerebrovascular disease | journal = Cardiovascular Psychiatry and Neurology | volume = 2009 | pages = 1–9 | year = 2009 | pmid = 20029618 | doi = 10.1155/2009/282059 | pmc=2790135| doi-access = free }}</ref>

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.<ref name=pmid21894646 /> But it is not clear whether this could be a direct or casual association or link between serum uric acid concentration (and by proxy, xanthine oxidase activity) and cardiovascular health.<ref name="J. Dawson et al">{{cite journal | vauthors = Dawson J, Quinn T, Walters M | title = Uric acid reduction: a new paradigm in the management of cardiovascular risk? | journal = Current Medicinal Chemistry | volume = 14 | issue = 17 | pages = 1879–86 | year = 2007 | pmid = 17627523 | doi = 10.2174/092986707781058797 }}</ref> States of high cell turnover and alcohol ingestion are some of the most prominent cases of high serum uric acid concentrations.<ref name="P. Higgins et al." />

Reactive nitrogen species, such as peroxynitrite that xanthine oxidase can form, have been found to react with DNA, proteins, and cells, causing cellular damage or even toxicity. Reactive nitrogen signaling, coupled with reactive oxygen species, have been found to be a central part of myocardial and vascular function, explaining why xanthine oxidase is being researched for links to cardiovascular health.<ref name="JM Zimmet & JM Hare">{{cite journal | vauthors = Zimmet JM, Hare JM | title = Nitroso-redox interactions in the cardiovascular system | journal = Circulation | volume = 114 | issue = 14 | pages = 1531–44 | date = October 2006 | pmid = 17015805 | doi = 10.1161/CIRCULATIONAHA.105.605519 | s2cid = 1572496 | doi-access = free }}</ref>

Both xanthine oxidase and xanthine [[oxidoreductase]] are also present in [[cornea]]l epithelium and endothelium and may be involved in oxidative eye injury.<ref name="pmid12168784">{{cite journal | vauthors = Cejková J, Ardan T, Filipec M, Midelfart A | title = Xanthine oxidoreductase and xanthine oxidase in human cornea | journal = Histology and Histopathology | volume = 17 | issue = 3 | pages = 755–60 | year = 2002 | pmid = 12168784 | doi =  10.14670/HH-17.755}}</ref>

==Inhibitors==
{{main|Xanthine oxidase inhibitor}}
Inhibitors of XO include [[allopurinol]],<ref name="pmid16507884">{{cite journal | vauthors = Pacher P, Nivorozhkin A, Szabó C | title = Therapeutic effects of xanthine oxidase inhibitors: renaissance half a century after the discovery of allopurinol | journal = Pharmacological Reviews | volume = 58 | issue = 1 | pages = 87–114 | date = March 2006 | pmid = 16507884 | pmc = 2233605 | doi = 10.1124/pr.58.1.6 }}</ref> [[oxypurinol]],<ref name="pmid2829916">{{cite journal | vauthors = Spector T | title = Oxypurinol as an inhibitor of xanthine oxidase-catalyzed production of superoxide radical | journal = Biochemical Pharmacology | volume = 37 | issue = 2 | pages = 349–52 | date = Jan 1988 | pmid = 2829916 | doi = 10.1016/0006-2952(88)90739-3 }}</ref> and [[phytic acid]].<ref name="pmid14738912">{{cite journal | vauthors = Muraoka S, Miura T | title = Inhibition of xanthine oxidase by phytic acid and its antioxidative action | journal = Life Sciences | volume = 74 | issue = 13 | pages = 1691–700 | date = February 2004 | pmid = 14738912 | doi = 10.1016/j.lfs.2003.09.040 }}</ref> It has also been found to be inhibited by [[flavonoids]],<ref name="Cos et al.">{{cite journal | vauthors = Cos P, Ying L, Calomme M, Hu JP, Cimanga K, Van Poel B, Pieters L, Vlietinck AJ, Vanden Berghe D | title = Structure-activity relationship and classification of flavonoids as inhibitors of xanthine oxidase and superoxide scavengers | journal = Journal of Natural Products | volume = 61 | issue = 1 | pages = 71–6 | date = Jan 1998 | pmid = 9461655 | doi = 10.1021/np970237h }}</ref> including those found in ''[[Bougainvillea spectabilis]]'' ([[Nyctaginaceae]]) leaves (with an [[IC50|IC<sub>50</sub>]] of 7.23&nbsp;μM), typically used in [[folk medicine]].<ref name="Chang, WS">{{cite journal | vauthors = Chang WS, Lee YJ, Lu FJ, Chiang HC | title = Inhibitory effects of flavonoids on xanthine oxidase | journal = Anticancer Research | volume = 13 | issue = 6A | pages = 2165–70 | date = Nov–Dec 1993 | pmid = 8297130 }}</ref>

==See also==
* [[Xanthine dehydrogenase]]
* [[Sodium molybdate]]

==References==
{{Reflist}}

==External links==
* {{MeshName|Xanthine+Oxidase}}

{{Nucleotide metabolism}}
{{Other oxidoreductases}}
{{Enzymes}}
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[[Category:EC 1.17.3]]
[[Category:Metalloproteins]]
[[Category:Molybdenum enzymes]]
[[Category:Iron-sulfur enzymes]]
[[Category:Superoxide generating substances]]