Urate oxidase

Last updated
UOX
Identifiers
Aliases UOX , UOXP, URICASE, Urate oxidase, urate oxidase (pseudogene)
External IDs MGI: 98907; GeneCards: UOX; OMA:UOX - orthologs
Orthologs
SpeciesHumanMouse
Entrez

391051

22262

Ensembl

ENSG00000240520

ENSMUSG00000028186

UniProt

n
a

P25688

RefSeq (mRNA)

n/a

NM_009474

RefSeq (protein)

n/a

NP_033500

Location (UCSC)n/a Chr 3: 146.28 – 146.34 Mb
PubMed search [2] [3]
Wikidata
View/Edit Human View/Edit Mouse

The enzyme urate oxidase (UO), uricase or factor-independent urate hydroxylase, absent in humans, catalyzes the oxidation of uric acid to 5-hydroxyisourate: [4]

Contents

Uric acid + O2 + H2O → 5-hydroxyisourate + H2O2
5-hydroxyisourate + H2O → 2-oxo-4-hydroxy-4-carboxy-5-ureidoimidazoline
2-oxo-4-hydroxy-4-carboxy-5-ureidoimidazoline → allantoin + CO2
sequence of oxidation of ureate. UreateOxidaseRxn.svg
sequence of oxidation of ureate.

Structure

Urate oxidase is mainly localised in the liver, where it forms a large electron-dense paracrystalline core in many peroxisomes. [5] The enzyme exists as a tetramer of identical subunits, each containing a possible type 2 copper-binding site. [6]

Urate oxidase is a homotetrameric enzyme containing four identical active sites situated at the interfaces between its four subunits. UO from A. flavus is made up of 301 residues and has a molecular weight of 33438 daltons. It is unique among the oxidases in that it does not require a metal atom or an organic co-factor for catalysis. Sequence analysis of several organisms has determined that there are 24 amino acids which are conserved, and of these, 15 are involved with the active site.

factor-independent urate hydroxylase
Identifiers
EC no. 1.7.3.3
CAS no. 9002-12-4
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
Search
PMC articles
PubMed articles
NCBI proteins
Uricase
Identifiers
SymbolUricase
Pfam PF01014
InterPro IPR002042
PROSITE PDOC00315
SCOP2 1uox / SCOPe / SUPFAM
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary
PDB 1ws2 D:142-291 1r56 A:142-291 1ws3 B:142-291 1xxj D:142-291 1xt4 A:142-291 1r4u A:142-291 1r51 A:142-291 1r4s A:142-291 1j2g B:336-476

Reaction mechanism

Urate oxidase is the first enzyme in a pathway of three enzymes to convert uric acid to S-(+)-allantoin. After uric acid is converted to 5-hydroxyisourate by urate oxidase, 5-hydroxyisourate (HIU) is converted to 2-oxo-4-hydroxy-4-carboxy-5-ureidoimidazoline (OHCU) by HIU hydrolase, and then to S-(+)-allantoin by 2-oxo-4-hydroxy-4-carboxy-5-ureidoimidazoline decarboxylase (OHCU decarboxylase). Without HIU hydrolase and OHCU decarboxylase, HIU will spontaneously decompose into racemic allantoin. [7]

The active site binds uric acid (and its analogues), allowing it to interact with O2. [8] According to X-ray crystallography, it is the conjugate base of uric acid that binds and is then deprotonated to a dianion. The dianion is stabilized by extensive hydrogen-bonding, e.g., to Arg 176 and Gln 228 . [9] Oxygen accepts two electrons from the urate dianion, via a sequence of one-electron transfers, ultimately yielding hydrogen peroxide and the dehydrogenated substrate. The dehydrourate adds water (hydrates) to produce 5-hydroxyisourate. [10]

Urate oxidase is known to be inhibited by both cyanide and chloride ions. Inhibition involves anion-π interactions between the inhibitor and the uric acid substrate. [11]

Significance of absence in humans

Urate oxidase is found in nearly all organisms, from bacteria to mammals, but is inactive in humans and all apes (great and lesser apes), having been lost in hominoid ancestors during primate evolution. [6] This means that instead of producing allantoin as the end product of purine oxidation, the pathway ends with uric acid. This leads to humans having much higher and more highly variable levels of urate in the blood than most other mammals. [12]

Genetically, the loss of urate oxidase function in humans was caused by two nonsense mutations at codons 33 and 187 and an aberrant splice site. [13]

It has been proposed that the loss of urate oxidase gene expression has been advantageous to hominoids, since uric acid is a powerful antioxidant and scavenger of singlet oxygen and radicals. Its presence provides the body with protection from oxidative damage, thus prolonging life and decreasing age-specific cancer rates. [14]

However, uric acid plays a complex physiological role in several processes, including inflammation and danger signalling, [15] and modern purine-rich diets can lead to hyperuricaemia, which is linked to many diseases including an increased risk of developing gout. [12]

Medical uses

Urate oxidase is formulated as a protein drug (rasburicase) for the treatment of acute hyperuricemia in patients receiving chemotherapy. A PEGylated form of urate oxidase, pegloticase, was FDA approved in 2010 for the treatment of chronic gout in adult patients refractory to "conventional therapy". [16]

Disease relevance

Children with non-Hodgkin's lymphoma (NHL), specifically with Burkitt's lymphoma and B-cell acute lymphoblastic leukemia (B-ALL), often experience tumor lysis syndrome (TLS), which occurs when breakdown of tumor cells by chemotherapy releases uric acid and cause the formation of uric acid crystals in the renal tubules and collecting ducts. This can lead to kidney failure and even death. Studies suggest that patients at a high risk of developing TLS may benefit from the administration of urate oxidase. [17] However, humans lack the subsequent enzyme HIU hydroxylase in the pathway to degrade uric acid to allantoin, so long-term urate oxidase therapy could potentially have harmful effects because of toxic effects of HIU. [18]

Higher uric acid levels have also been associated with epilepsy. However, it was found in mouse models that disrupting urate oxidase actually decreases brain excitability and susceptibility to seizures. [19]

Graft-versus-host disease (GVHD) is often a side effect of allogeneic hematopoietic stem cell transplantation (HSCT), driven by donor T cells destroying host tissue. Uric acid has been shown to increase T cell response, so clinical trials have shown that urate oxidase can be administered to decrease uric acid levels in the patient and subsequently decrease the likelihood of GVHD. [20]

In legumes

UO is also an essential enzyme in the ureide pathway, where nitrogen fixation occurs in the root nodules of legumes. The fixed nitrogen is converted to metabolites that are transported from the roots throughout the plant to provide the needed nitrogen for amino acid biosynthesis.

In legumes, 2 forms of uricase are found: in the roots, the tetrameric form; and, in the uninfected cells of root nodules, a monomeric form, which plays an important role in nitrogen-fixation. [21]

Convergent evolution

Urate oxidase is a notable example of the existence of non-homologous isofunctional enzymes, proteins with independent evolutionary origin catalyzing the same chemical reaction.

Besides the cofactorless urate oxidase (UOX), which is found in all three domains of life, other bacterial proteins are known that catalyze the same reaction without being evolutionarily related to UOX. These are two different oxidases (named HpxO and HpyO) that use FAD and NAD+ as cofactors, and one integral membrane protein (named PuuD) that additionally contains a cytochrome c protein domain. [22]

See also

Related Research Articles

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 oxidase</span> Class of enzymes

Xanthine oxidase 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.

<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">Eicosanoid</span> Class of compounds

Eicosanoids are signaling molecules made by the enzymatic or non-enzymatic oxidation of arachidonic acid or other polyunsaturated fatty acids (PUFAs) that are, similar to arachidonic acid, around 20 carbon units in length. Eicosanoids are a sub-category of oxylipins, i.e. oxidized fatty acids of diverse carbon units in length, and are distinguished from other oxylipins by their overwhelming importance as cell signaling molecules. Eicosanoids function in diverse physiological systems and pathological processes such as: mounting or inhibiting inflammation, allergy, fever and other immune responses; regulating the abortion of pregnancy and normal childbirth; contributing to the perception of pain; regulating cell growth; controlling blood pressure; and modulating the regional flow of blood to tissues. In performing these roles, eicosanoids most often act as autocrine signaling agents to impact their cells of origin or as paracrine signaling agents to impact cells in the proximity of their cells of origin. Some eicosanoids, such as prostaglandins, may also have endocrine roles as hormones to influence the function of distant cells.

<span class="mw-page-title-main">Pyridoxal phosphate</span> Active form of vitamin B6

Pyridoxal phosphate (PLP, pyridoxal 5'-phosphate, P5P), the active form of vitamin B6, is a coenzyme in a variety of enzymatic reactions. The International Union of Biochemistry and Molecular Biology has catalogued more than 140 PLP-dependent activities, corresponding to ~4% of all classified activities. The versatility of PLP arises from its ability to covalently bind the substrate, and then to act as an electrophilic catalyst, thereby stabilizing different types of carbanionic reaction intermediates.

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

Allantoin is a chemical compound with formula C4H6N4O3. It is also called 5-ureidohydantoin or glyoxyldiureide. It is a diureide of glyoxylic acid. Allantoin is a major metabolic intermediate in most organisms including animals, plants and bacteria. It is produced from uric acid, which itself is a degradation product of nucleic acids, by action of urate oxidase (uricase). Allantoin also occurs as a natural mineral compound (IMA symbol Aan).

<span class="mw-page-title-main">Rasburicase</span> Pharmaceutical drug

Rasburicase, sold under the brand name Elitek in the US and Fasturtec in the EU, is a medication that helps to clear uric acid from the blood. It is a recombinant version of urate oxidase, an enzyme that metabolizes uric acid to allantoin. Urate oxidase is known to be present in many mammals but does not naturally occur in humans. Rasburicase is produced by a genetically modified Saccharomyces cerevisiae strain. The complementary DNA (cDNA) coding for rasburicase was cloned from a strain of Aspergillus flavus.

<span class="mw-page-title-main">Oxidative stress</span> Free radical toxicity

Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage. Disturbances in the normal redox state of cells can cause toxic effects through the production of peroxides and free radicals that damage all components of the cell, including proteins, lipids, and DNA. Oxidative stress from oxidative metabolism causes base damage, as well as strand breaks in DNA. Base damage is mostly indirect and caused by the reactive oxygen species generated, e.g., O−
2, OH and H2O2. Further, some reactive oxidative species act as cellular messengers in redox signaling. Thus, oxidative stress can cause disruptions in normal mechanisms of cellular signaling.

Carboxy-lyases, also known as decarboxylases, are carbon–carbon lyases that add or remove a carboxyl group from organic compounds. These enzymes catalyze the decarboxylation of amino acids, beta-keto acids and alpha-keto acids.

<span class="mw-page-title-main">5-Hydroxyisourate</span> Chemical compound

5-Hydroxyisourate is an organic compound that is produced by the oxidation of uric acid. The conversion is a major pathway in the antioxidant properties of urate. The conversion is catalysed by urate oxidase.

Arachidonate 5-lipoxygenase, also known as ALOX5, 5-lipoxygenase, 5-LOX, or 5-LO, is a non-heme iron-containing enzyme that in humans is encoded by the ALOX5 gene. Arachidonate 5-lipoxygenase is a member of the lipoxygenase family of enzymes. It transforms essential fatty acids (EFA) substrates into leukotrienes as well as a wide range of other biologically active products. ALOX5 is a current target for pharmaceutical intervention in a number of diseases.

<span class="mw-page-title-main">(S)-2-hydroxy-acid oxidase</span> Class of enzymes

In enzymology, an (S)-2-hydroxy-acid oxidase (EC 1.1.3.15) is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">Diphosphomevalonate decarboxylase</span> InterPro Family

Diphosphomevalonate decarboxylase (EC 4.1.1.33), most commonly referred to in scientific literature as mevalonate diphosphate decarboxylase, is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">Oxalyl-CoA decarboxylase</span>

The enzyme oxalyl-CoA decarboxylase (OXC) (EC 4.1.1.8), primarily produced by the gastrointestinal bacterium Oxalobacter formigenes, catalyzes the chemical reaction

In enzymology, a hydroxyisourate hydrolase (EC 3.5.2.17) is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">5-Hydroxyeicosatetraenoic acid</span> Chemical compound

5-Hydroxyeicosatetraenoic acid (5-HETE, 5(S)-HETE, or 5S-HETE) is an eicosanoid, i.e. a metabolite of arachidonic acid. It is produced by diverse cell types in humans and other animal species. These cells may then metabolize the formed 5(S)-HETE to 5-oxo-eicosatetraenoic acid (5-oxo-ETE), 5(S),15(S)-dihydroxyeicosatetraenoic acid (5(S),15(S)-diHETE), or 5-oxo-15-hydroxyeicosatetraenoic acid (5-oxo-15(S)-HETE).

In molecular biology 2-oxo-4-hydroxy-4-carboxy-5-ureidoimidazoline decarboxylase EC 4.1.1.n1 is an enzyme involved in purine catabolism. It catalyses the decarboxylation of 2-oxo-4-hydroxy-4-carboxy-5-ureidoimidazoline (OHCU) into S(+)-allantoin. It is the third step of the conversion of uric acid to allantoin. Step one is catalysed by urate oxidase and step two is catalysed by hydroxyisourate hydrolase.

2-hydroxy-dATP diphosphatase is an enzyme that in humans is encoded by the NUDT1 gene. During DNA repair, the enzyme hydrolyses oxidized purines and prevents their addition onto the DNA chain. As such it has important role in aging and cancer development.

Bacillus fastidiosus is an aerobic, motile, rod-shaped bacterium that has been isolated from soil and poultry litter. The species was first isolated and described by the scientist Den Dooren de Jong in 1929. This organism is a mesophile that contains ellipsoidal spores that do not cause swelling of the sporangia. Bacillus fastidiosus is only able to grow in the presence of uric acid, allantoin, or allantoic acid.

<span class="mw-page-title-main">15-Hydroxyeicosatetraenoic acid</span> Chemical compound

15-Hydroxyeicosatetraenoic acid (also termed 15-HETE, 15(S)-HETE, and 15S-HETE) is an eicosanoid, i.e. a metabolite of arachidonic acid. Various cell types metabolize arachidonic acid to 15(S)-hydroperoxyeicosatetraenoic acid (15(S)-HpETE). This initial hydroperoxide product is extremely short-lived in cells: if not otherwise metabolized, it is rapidly reduced to 15(S)-HETE. Both of these metabolites, depending on the cell type which forms them, can be further metabolized to 15-oxo-eicosatetraenoic acid (15-oxo-ETE), 5(S),15(S)-dihydroxy-eicosatetraenoic acid (5(S),15(S)-diHETE), 5-oxo-15(S)-hydroxyeicosatetraenoic acid (5-oxo-15(S)-HETE), a subset of specialized pro-resolving mediators viz., the lipoxins, a class of pro-inflammatory mediators, the eoxins, and other products that have less well-defined activities and functions. Thus, 15(S)-HETE and 15(S)-HpETE, in addition to having intrinsic biological activities, are key precursors to numerous biologically active derivatives.

References

  1. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000028186 – Ensembl, May 2017
  2. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  3. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ Motojima K, Kanaya S, Goto S (November 1988). "Cloning and sequence analysis of cDNA for rat liver uricase". The Journal of Biological Chemistry. 263 (32): 16677–81. doi: 10.1016/S0021-9258(18)37443-X . PMID   3182808.
  5. ↑ Motojima K, Goto S (May 1990). "Organization of rat uricase chromosomal gene differs greatly from that of the corresponding plant gene". FEBS Letters. 264 (1): 156–8. Bibcode:1990FEBSL.264..156M. doi:10.1016/0014-5793(90)80789-L. PMID   2338140. S2CID   36132942.
  6. 1 2 Wu XW, Lee CC, Muzny DM, Caskey CT (December 1989). "Urate oxidase: primary structure and evolutionary implications". Proceedings of the National Academy of Sciences of the United States of America. 86 (23): 9412–6. Bibcode:1989PNAS...86.9412W. doi: 10.1073/pnas.86.23.9412 . PMC   298506 . PMID   2594778.
  7. ↑ Ramazzina I, Folli C, Secchi A, Berni R, Percudani R (March 2006). "Completing the uric acid degradation pathway through phylogenetic comparison of whole genomes". Nature Chemical Biology. 2 (3): 144–8. doi:10.1038/nchembio768. PMID   16462750. S2CID   13441301.
  8. ↑ Gabison L, Prangé T, Colloc'h N, El Hajji M, Castro B, Chiadmi M (July 2008). "Structural analysis of urate oxidase in complex with its natural substrate inhibited by cyanide: mechanistic implications". BMC Structural Biology. 8: 32. doi: 10.1186/1472-6807-8-32 . PMC   2490695 . PMID   18638417.
  9. ↑ Colloc'h N, el Hajji M, Bachet B, L'Hermite G, Schiltz M, Prangé T, Castro B, Mornon JP (November 1997). "Crystal structure of the protein drug urate oxidase-inhibitor complex at 2.05 A resolution". Nature Structural Biology. 4 (11): 947–52. doi:10.1038/nsb1197-947. PMID   9360612. S2CID   1282767.
  10. ↑ Oksanen E, Blakeley MP, El-Hajji M, Ryde U, Budayova-Spano M (2014-01-23). "The Neutron Structure of Urate Oxidase Resolves a Long-Standing Mechanistic Conundrum and Reveals Unexpected Changes in Protonation". PLOS ONE. 9 (1): e86651. Bibcode:2014PLoSO...986651O. doi: 10.1371/journal.pone.0086651 . PMC   3900588 . PMID   24466188.
  11. ↑ Estarellas C, Frontera A, Quiñonero D, Deyà PM (January 2011). "Relevant anion-π interactions in biological systems: the case of urate oxidase". Angewandte Chemie. 50 (2): 415–8. doi:10.1002/anie.201005635. PMID   21132687.
  12. 1 2 So A, Thorens B (June 2010). "Uric acid transport and disease". The Journal of Clinical Investigation. 120 (6): 1791–9. doi:10.1172/JCI42344. PMC   2877959 . PMID   20516647.
  13. ↑ Wu XW, Muzny DM, Lee CC, Caskey CT (January 1992). "Two independent mutational events in the loss of urate oxidase during hominoid evolution". Journal of Molecular Evolution. 34 (1): 78–84. Bibcode:1992JMolE..34...78W. doi:10.1007/BF00163854. PMID   1556746. S2CID   33424555.
  14. ↑ Ames BN, Cathcart R, Schwiers E, Hochstein P (November 1981). "Uric acid provides an antioxidant defense in humans against oxidant- and radical-caused aging and cancer: a hypothesis". Proceedings of the National Academy of Sciences of the United States of America. 78 (11): 6858–62. Bibcode:1981PNAS...78.6858A. doi: 10.1073/pnas.78.11.6858 . PMC   349151 . PMID   6947260.
  15. ↑ Ghaemi-Oskouie F, Shi Y (April 2011). "The role of uric acid as an endogenous danger signal in immunity and inflammation". Current Rheumatology Reports. 13 (2): 160–6. doi:10.1007/s11926-011-0162-1. PMC   3093438 . PMID   21234729.
  16. ↑ "Pegloticase Drug Approval Package". US FDA. Retrieved 15 May 2017.
  17. ↑ Wössmann W, Schrappe M, Meyer U, Zimmermann M, Reiter A (March 2003). "Incidence of tumor lysis syndrome in children with advanced stage Burkitt's lymphoma/leukemia before and after introduction of prophylactic use of urate oxidase". Annals of Hematology. 82 (3): 160–5. doi:10.1007/s00277-003-0608-2. PMID   12634948. S2CID   27279071.
  18. ↑ Stevenson WS, Hyland CD, Zhang JG, Morgan PO, Willson TA, Gill A, Hilton AA, Viney EM, Bahlo M, Masters SL, Hennebry S, Richardson SJ, Nicola NA, Metcalf D, Hilton DJ, Roberts AW, Alexander WS (September 2010). "Deficiency of 5-hydroxyisourate hydrolase causes hepatomegaly and hepatocellular carcinoma in mice". Proceedings of the National Academy of Sciences of the United States of America. 107 (38): 16625–30. Bibcode:2010PNAS..10716625S. doi: 10.1073/pnas.1010390107 . PMC   2944704 . PMID   20823251.
  19. ↑ Thyrion L, Portelli J, Raedt R, Glorieux G, Larsen LE, Sprengers M, Van Lysebettens W, Carrette E, Delbeke J, Vonck K, Boon P (July 2016). "Disruption, but not overexpression of urate oxidase alters susceptibility to pentylenetetrazole- and pilocarpine-induced seizures in mice". Epilepsia. 57 (7): e146-50. doi: 10.1111/epi.13410 . PMID   27158916.
  20. ↑ Yeh AC, Brunner AM, Spitzer TR, Chen YB, Coughlin E, McAfee S, Ballen K, Attar E, Caron M, Preffer FI, Yeap BY, Dey BR (May 2014). "Phase I study of urate oxidase in the reduction of acute graft-versus-host disease after myeloablative allogeneic stem cell transplantation". Biology of Blood and Marrow Transplantation. 20 (5): 730–4. doi: 10.1016/j.bbmt.2014.02.003 . PMID   24530972.
  21. ↑ Nguyen T, Zelechowska M, Foster V, Bergmann H, Verma DP (August 1985). "Primary structure of the soybean nodulin-35 gene encoding uricase II localized in the peroxisomes of uninfected cells of nodules". Proceedings of the National Academy of Sciences of the United States of America. 82 (15): 5040–4. Bibcode:1985PNAS...82.5040N. doi: 10.1073/pnas.82.15.5040 . PMC   390494 . PMID   16593585.
  22. ↑ Doniselli, N.; Monzeglio, E.; Dal Palù, A.; Merli, A.; Percudani, R. (2015). "The identification of an integral membrane, cytochrome c urate oxidase completes the catalytic repertoire of a therapeutic enzyme". Scientific Reports. 5: 13798. Bibcode:2015NatSR...513798D. doi:10.1038/srep13798. PMC   4562309 . PMID   26349049.
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