Urate oxidase

The enzyme urate oxidase (UO), or uricase or factor-independent urate hydroxylase, absent in humans, catalyzes the oxidation of uric acid to 5-hydroxyisourate:^[1]

Uric acid + O₂ + H₂O → 5-hydroxyisourate + H₂O₂ → allantoin + CO₂

Uric acid

5-hydroxyisourate

Allantoin

Structure

Urate oxidase is mainly localised in the liver, where it forms a large electron-dense paracrystalline core in many peroxisomes.^[2] The enzyme exists as a tetramer of identical subunits, each containing a possible type 2 copper-binding site.^[3]

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 dalton. 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

Databases

PDB structures

AmiGO / EGO

Search
PMC	articles
PubMed	articles
NCBI	proteins

Uricase

Identifiers

Symbol

Uricase

Available protein structures:
Pfam	structures
PDB	RCSB PDB; PDBe; PDBj
PDBsum	structure summary

Significance of absence in humans

Humans do have a gene for urate oxidase, but it is nonfunctional. Thus uric acid is the end product of catabolism of purines in humans. Excessive concentration of uric acid in the blood stream leads to gout.

Urate oxidase is found in nearly all organisms, from bacteria to mammals, and plays different metabolic roles, depending on its host organism. It was lost in early primate evolution,^[3] and so is absent in humans and other higher apes.

It has been proposed that the loss of urate oxidase gene expression has been advantageous to hominids, since uric acid is a powerful antioxidant and scavenger of singlet oxygen and radicals.^[4] Its presence provides the body with protection from oxidative damage, thus prolonging life and decreasing age-specific cancer rates. However, this is highly unlikely as proteins are capable of being activated only when concentrations exceed a certain amount. Adequate uric acid levels could still be maintained to protect the body while preventing evolutionarily disadvantageous conditions like gout.

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 is in clinical development for treatment of chronic hyperuricemia in patients with "treatment-failure gout".

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.^[5]

References

↑ Motojima K, Goto S, Kanaya S (1988). "Cloning and sequence analysis of cDNA for rat liver uricase". J. Biol. Chem. 263 (32): 16677–16681. PMID 3182808.
↑ Motojima K, Goto S (1990). "Organization of rat uricase chromosomal gene differs greatly from that of the corresponding plant gene". FEBS Lett. 264 (1): 156–158. doi:10.1016/0014-5793(90)80789-L. PMID 2338140.
1 2 Lee CC, Caskey CT, Wu XW, Muzny DM (1989). "Urate oxidase: primary structure and evolutionary implications". Proc. Natl. Acad. Sci. U.S.A. 86 (23): 9412–9416. doi:10.1073/pnas.86.23.9412. PMC 298506. PMID 2594778.
↑ 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". Proc. Natl. Acad. Sci. U.S.A. 78 (11): 6858–62. doi:10.1073/pnas.78.11.6858. PMC 349151. PMID 6947260.
↑ Nguyen T, Zelechowska M, Foster V, Bergmann H, Verma DPS (1985). "Primary structure of the soybean nodulin-35 gene encoding uricase II localized in the peroxisomes of uninfected cells of nodules". Proc. Natl. Acad. Sci. U.S.A. 82 (15): 5040–5044. doi:10.1073/pnas.82.15.5040. PMC 390494. PMID 16593585.

Purine metabolism

Anabolism

R5P→IMP:	Ribose-phosphate diphosphokinase Amidophosphoribosyltransferase Phosphoribosylglycinamide formyltransferase AIR synthetase (FGAM cyclase) Phosphoribosylaminoimidazole carboxylase Phosphoribosylaminoimidazolesuccinocarboxamide synthase IMP synthase

IMP→AMP:	Adenylosuccinate synthase Adenylosuccinate lyase reverse AMP deaminase

IMP→GMP:	IMP dehydrogenase GMP synthase reverse GMP reductase

Nucleotide salvage

Catabolism

Pyrimidine metabolism

Anabolism

CAD Carbamoyl phosphate synthase II Aspartate carbamoyltransferase Dihydroorotase

Dihydroorotate dehydrogenase Orotidine 5'-phosphate decarboxylase/Uridine monophosphate synthetase

CTP synthetase

Catabolism

Deoxyribonucleotides

Oxidoreductases: nitrogenous donor (EC 1.7)

1.7.1	GMP reductase

1.7.2	Nitrite reductase (NO-forming)

1.7.3	Urate oxidase

1.7.7	Ferredoxin—nitrite reductase

1.7.99	Hydroxylamine reductase

Enzymes

Activity	Active site Binding site Catalytic triad Oxyanion hole Enzyme promiscuity Catalytically perfect enzyme Coenzyme Cofactor Enzyme catalysis Enzyme kinetics Lineweaver–Burk plot Michaelis–Menten kinetics

Regulation	Allosteric regulation Cooperativity Enzyme inhibitor

Classification	EC number Enzyme superfamily Enzyme family List of enzymes

Types	EC1 Oxidoreductases(list) EC2 Transferases(list) EC3 Hydrolases(list) EC4 Lyases(list) EC5 Isomerases(list) EC6 Ligases(list)

This article incorporates text from the public domain Pfam and InterPro IPR002042

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