Urate oxidase
UOX | ||||||
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Location (UCSC) | n/a | Chr 3: 146.28 – 146.34 Mb | ||||
PubMed search | [2] | [3] |
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The enzyme urate oxidase (UO), uricase or factor-independent urate hydroxylase, absent in humans, catalyzes the
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.
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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 ineract 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
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
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
This section needs more primary sources. (March 2018) |
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
This section needs more primary sources. (March 2018) |
Children with
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]
See also
References
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000028186 - Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- PMID 3182808.
- S2CID 36132942.
- ^ PMID 2594778.
- S2CID 13441301.
- PMID 18638417.
- S2CID 1282767.
- PMID 24466188.
- PMID 21132687.
- ^ PMID 20516647.
- S2CID 33424555.
- PMID 6947260.
- PMID 21234729.
- ^ "Pegloticase Drug Approval Package". US FDA. Retrieved 15 May 2017.
- S2CID 27279071.
- PMID 20823251.
- PMID 27158916.
- PMID 24530972.
- PMID 16593585.