Xanthine oxidase

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xanthine oxidase/dehydrogenase
XanthineOxidase-1FIQ.png
Crystallographic structure (monomer) of bovine xanthine oxidase. [1]
The bounded FAD (red), FeS-cluster (orange), the molybdopterin cofactor with molybdenum (yellow) and salicylate (blue) are indicated.
Identifiers
EC no. 1.17.3.2
CAS no. 9002-17-9
Databases
IntEnz IntEnz view
BRENDA BRENDA entry
ExPASy NiceZyme view
KEGG KEGG entry
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
Gene Ontology AmiGO / QuickGO
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PMC articles
PubMed articles
NCBI proteins
xanthine oxidase/dehydrogenase
Identifiers
Symbol XDH
NCBI gene 7498
HGNC 12805
OMIM 607633
PDB 1FIQ
RefSeq NM_000379
UniProt P47989
Other data
EC number 1.17.3.2
Locus Chr. 2 p23.1
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Structures Swiss-model
Domains InterPro

Xanthine oxidase (XO, sometimes 'XAO') is a form of xanthine oxidoreductase, a type of enzyme that generates reactive oxygen species. [2] 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. [3]

Contents

Xanthine oxidase is defined as an enzyme activity (EC 1.17.3.2). [4] The same protein, which in humans has the HGNC approved gene symbol XDH, can also have xanthine dehydrogenase activity (EC 1.17.1.4). [5] 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. [6] [7]

Reaction

The following chemical reactions are catalyzed by xanthine oxidase:

Other reactions

Because XO is a superoxide-producing enzyme, with general low specificity, [9] 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. [10]

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. [11]

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. [9]

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

Xanthine oxidase pathways.jpg

It is suggested that xanthine oxidoreductase, along with other enzymes, participates in the conversion of nitrate to nitrite in mammalian tissues. [12]

Protein structure

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.

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. [3] Like other known molybdenum-containing oxidoreductases, the oxygen atom introduced to the substrate by XO originates from water rather than from dioxygen (O2).

Clinical significance

Xanthine oxidase is a superoxide-producing enzyme found normally in serum and the lungs, and its activity is increased during influenza A infection. [13]

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. [14]

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). [15]

Inhibition of xanthine oxidase has been proposed as a mechanism for improving cardiovascular health. [16] 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. [17] Oxidative stress can be caused by hydroxyl free radicals and hydrogen peroxide, both of which are byproducts of XO activity. [18]

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. [16] 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. [19] States of high cell turnover and alcohol ingestion are some of the most prominent cases of high serum uric acid concentrations. [18]

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. [20]

Both xanthine oxidase and xanthine oxidoreductase are also present in corneal epithelium and endothelium and may be involved in oxidative eye injury. [21]

Inhibitors

Inhibitors of XO include allopurinol, [22] oxypurinol, [23] and phytic acid. [24] It has also been found to be inhibited by flavonoids, [25] including those found in Bougainvillea spectabilis (Nyctaginaceae) leaves (with an IC50 of 7.23 μM), typically used in folk medicine. [26]

See also

Related Research Articles

<span class="mw-page-title-main">Oxidative phosphorylation</span> Metabolic pathway

Oxidative phosphorylation or electron transport-linked phosphorylation or terminal oxidation is the metabolic pathway in which cells use enzymes to oxidize nutrients, thereby releasing chemical energy in order to produce adenosine triphosphate (ATP). In eukaryotes, this takes place inside mitochondria. Almost all aerobic organisms carry out oxidative phosphorylation. This pathway is so pervasive because it releases more energy than alternative fermentation processes such as anaerobic glycolysis.

<span class="mw-page-title-main">Uric acid</span> Organic compound

Uric acid is a heterocyclic compound of carbon, nitrogen, oxygen, and hydrogen with the formula C5H4N4O3. It forms ions and salts known as urates and acid urates, such as ammonium acid urate. Uric acid is a product of the metabolic breakdown of purine nucleotides, and it is a normal component of urine. High blood concentrations of uric acid can lead to gout and are associated with other medical conditions, including diabetes and the formation of ammonium acid urate kidney stones.

<span class="mw-page-title-main">Xanthine</span> Chemical compound

Xanthine is a purine base found in most human body tissues and fluids, as well as in other organisms. Several stimulants are derived from xanthine, including caffeine, theophylline, and theobromine.

A dehydrogenase is an enzyme belonging to the group of oxidoreductases that oxidizes a substrate by reducing an electron acceptor, usually NAD+/NADP+ or a flavin coenzyme such as FAD or FMN. Like all catalysts, they catalyze reverse as well as forward reactions, and in some cases this has physiological significance: for example, alcohol dehydrogenase catalyzes the oxidation of ethanol to acetaldehyde in animals, but in yeast it catalyzes the production of ethanol from acetaldehyde.

In chemistry, a superoxide is a compound that contains the superoxide ion, which has the chemical formula O−2. The systematic name of the anion is dioxide(1−). The reactive oxygen ion superoxide is particularly important as the product of the one-electron reduction of dioxygen O2, which occurs widely in nature. Molecular oxygen (dioxygen) is a diradical containing two unpaired electrons, and superoxide results from the addition of an electron which fills one of the two degenerate molecular orbitals, leaving a charged ionic species with a single unpaired electron and a net negative charge of −1. Both dioxygen and the superoxide anion are free radicals that exhibit paramagnetism. Superoxide was historically also known as "hyperoxide".

<span class="mw-page-title-main">Allopurinol</span> Medication

Allopurinol is a medication used to decrease high blood uric acid levels. It is specifically used to prevent gout, prevent specific types of kidney stones and for the high uric acid levels that can occur with chemotherapy. It is taken orally or intravenously.

<span class="mw-page-title-main">Xanthinuria</span> Medical condition

Xanthinuria, also known as xanthine oxidase deficiency, is a rare genetic disorder causing the accumulation of xanthine. It is caused by a deficiency of the enzyme xanthine oxidase.

NADPH oxidase is a membrane-bound enzyme complex that faces the extracellular space. It can be found in the plasma membrane as well as in the membranes of phagosomes used by neutrophil white blood cells to engulf microorganisms. Human isoforms of the catalytic component of the complex include NOX1, NOX2, NOX3, NOX4, NOX5, DUOX1, and DUOX2.

<span class="mw-page-title-main">Sulfite oxidase</span>

Sulfite oxidase is an enzyme in the mitochondria of all eukaryotes, with exception of the yeasts. It oxidizes sulfite to sulfate and, via cytochrome c, transfers the electrons produced to the electron transport chain, allowing generation of ATP in oxidative phosphorylation. This is the last step in the metabolism of sulfur-containing compounds and the sulfate is excreted.

<span class="mw-page-title-main">Aldehyde oxidase</span> Enzyme

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<span class="mw-page-title-main">Febuxostat</span> Chemical compound

Febuxostat, sold under the brand names Uloric among others, is a medication used long-term to treat gout due to high uric acid levels. It is generally recommended only for people who cannot take allopurinol. When initially started, medications such as NSAIDs are often recommended to prevent gout flares. It is taken by mouth.

<span class="mw-page-title-main">Xanthine dehydrogenase</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">Oxipurinol</span> Chemical compound

Oxipurinol is an inhibitor of xanthine oxidase. It is an active metabolite of allopurinol and it is cleared renally. In cases of renal disease, this metabolite will accumulate to toxic levels. By inhibiting xanthine oxidase, it reduces uric acid production. High serum uric acid levels may result in gout, kidney stones, and other medical conditions.

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<span class="mw-page-title-main">Caffeine dehydrogenase</span> Enzyme

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References

  1. ↑ PDB: 1FIQ ​; Enroth C, Eger BT, Okamoto K, Nishino T, Nishino T, Pai EF (September 2000). "Crystal structures of bovine milk xanthine dehydrogenase and xanthine oxidase: structure-based mechanism of conversion". Proceedings of the National Academy of Sciences of the United States of America. 97 (20): 10723–8. Bibcode:2000PNAS...9710723E. doi: 10.1073/pnas.97.20.10723 . PMC   27090 . PMID   11005854.
  2. ↑ Ardan T, Kovaceva J, Cejková J (February 2004). "Comparative histochemical and immunohistochemical study on xanthine oxidoreductase/xanthine oxidase in mammalian corneal epithelium". Acta Histochemica. 106 (1): 69–75. doi:10.1016/j.acthis.2003.08.001. PMID   15032331.
  3. 1 2 Hille R, Hall J, Basu P (April 2014). "The Mononuclear Molybdenum Enzymes". Chemical Reviews. 114 (7): 3963–4038. doi:10.1021/cr400443z. PMC   4080432 . PMID   24467397.
  4. ↑ "KEGG record for EC 1.17.3.2". Genome.jp. Retrieved 23 December 2017.
  5. 1 2 "KEGG record for EC 1.17.1.4". Genome.jp. Retrieved 23 December 2017.
  6. ↑ "Entrez Gene: XDH xanthine dehydrogenase" . Retrieved 23 December 2017.
  7. ↑ Online Mendelian Inheritance in Man (OMIM): Xanthine dehydrogenase; XDH - 607633
  8. ↑ Birkett DJ, Miners JO, Valente L, Lillywhite KJ, Day RO (February 1997). "1-Methylxanthine derived from caffeine as a pharmacodynamic probe of oxypurinol effect". British Journal of Clinical Pharmacology. 43 (2): 197–200. doi:10.1046/j.1365-2125.1997.53711.x. PMC   2042732 . PMID   9131954.
  9. 1 2 Bonini MG, Miyamoto S, Di Mascio P, Augusto O (December 2004). "Production of the carbonate radical anion during xanthine oxidase turnover in the presence of bicarbonate". The Journal of Biological Chemistry. 279 (50): 51836–43. doi: 10.1074/jbc.M406929200 . PMID   15448145. S2CID   20161424.
  10. ↑ McCord JM, Fridovich I (November 1968). "The reduction of cytochrome c by milk xanthine oxidase". The Journal of Biological Chemistry. 243 (21): 5753–60. doi: 10.1016/S0021-9258(18)91929-0 . PMID   4972775.
  11. ↑ Trujillo M, Alvarez MN, Peluffo G, Freeman BA, Radi R (April 1998). "Xanthine oxidase-mediated decomposition of S-nitrosothiols". The Journal of Biological Chemistry. 273 (14): 7828–34. doi: 10.1074/jbc.273.14.7828 . PMID   9525875. S2CID   10221482.
  12. ↑ Jansson EA, Huang L, Malkey R, Govoni M, Nihlén C, Olsson A, Stensdotter M, Petersson J, Holm L, Weitzberg E, Lundberg JO (2008). "A mammalian functional nitrate reductase that regulates nitrite and nitric oxide homeostasis". Nature Chemical Biology. 4 (7): 411–7. doi:10.1038/nchembio.92. PMID   18516050.
  13. ↑ Hemilä H (January 1992). "Vitamin C and the common cold" (PDF). The British Journal of Nutrition. 67 (1): 3–16. doi:10.1079/BJN19920004. PMID   1547201. S2CID   8285621. Archived from the original (PDF) on 3 March 2016. Retrieved 28 October 2011.
  14. ↑ Battelli MG, Musiani S, Valgimigli M, Gramantieri L, Tomassoni F, Bolondi L, Stirpe F (April 2001). "Serum xanthine oxidase in human liver disease". The American Journal of Gastroenterology. 96 (4): 1194–9. doi:10.1111/j.1572-0241.2001.03700.x. PMID   11316169. S2CID   36068630.
  15. ↑ Online Mendelian Inheritance in Man (OMIM): Xanthinuria, Type II; XAN2 - 603592
  16. 1 2 Dawson J, Walters M (December 2006). "Uric acid and xanthine oxidase: future therapeutic targets in the prevention of cardiovascular disease?". British Journal of Clinical Pharmacology. 62 (6): 633–44. doi:10.1111/j.1365-2125.2006.02785.x. PMC   1885190 . PMID   21894646.
  17. ↑ Heunks LM, Viña J, van Herwaarden CL, Folgering HT, Gimeno A, Dekhuijzen PN (December 1999). "Xanthine oxidase is involved in exercise-induced oxidative stress in chronic obstructive pulmonary disease". The American Journal of Physiology. 277 (6 Pt 2): R1697–704. doi:10.1152/ajpregu.1999.277.6.R1697. PMID   10600916. S2CID   4518363.
  18. 1 2 Higgins P, Dawson J, Walters M (2009). "The potential for xanthine oxidase inhibition in the prevention and treatment of cardiovascular and cerebrovascular disease". Cardiovascular Psychiatry and Neurology. 2009: 1–9. doi: 10.1155/2009/282059 . PMC   2790135 . PMID   20029618.
  19. ↑ Dawson J, Quinn T, Walters M (2007). "Uric acid reduction: a new paradigm in the management of cardiovascular risk?". Current Medicinal Chemistry. 14 (17): 1879–86. doi:10.2174/092986707781058797. PMID   17627523.
  20. ↑ Zimmet JM, Hare JM (October 2006). "Nitroso-redox interactions in the cardiovascular system". Circulation. 114 (14): 1531–44. doi: 10.1161/CIRCULATIONAHA.105.605519 . PMID   17015805. S2CID   1572496.
  21. ↑ Cejková J, Ardan T, Filipec M, Midelfart A (2002). "Xanthine oxidoreductase and xanthine oxidase in human cornea". Histology and Histopathology. 17 (3): 755–60. doi:10.14670/HH-17.755. PMID   12168784.
  22. ↑ Pacher P, Nivorozhkin A, Szabó C (March 2006). "Therapeutic effects of xanthine oxidase inhibitors: renaissance half a century after the discovery of allopurinol". Pharmacological Reviews. 58 (1): 87–114. doi:10.1124/pr.58.1.6. PMC   2233605 . PMID   16507884.
  23. ↑ Spector T (January 1988). "Oxypurinol as an inhibitor of xanthine oxidase-catalyzed production of superoxide radical". Biochemical Pharmacology. 37 (2): 349–52. doi:10.1016/0006-2952(88)90739-3. PMID   2829916.
  24. ↑ Muraoka S, Miura T (February 2004). "Inhibition of xanthine oxidase by phytic acid and its antioxidative action". Life Sciences. 74 (13): 1691–700. doi:10.1016/j.lfs.2003.09.040. PMID   14738912.
  25. ↑ Cos P, Ying L, Calomme M, Hu JP, Cimanga K, Van Poel B, Pieters L, Vlietinck AJ, Vanden Berghe D (January 1998). "Structure-activity relationship and classification of flavonoids as inhibitors of xanthine oxidase and superoxide scavengers". Journal of Natural Products. 61 (1): 71–6. doi:10.1021/np970237h. PMID   9461655.
  26. ↑ Chang WS, Lee YJ, Lu FJ, Chiang HC (November–December 1993). "Inhibitory effects of flavonoids on xanthine oxidase". Anticancer Research. 13 (6A): 2165–70. PMID   8297130.
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