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Urate oxidase Edit Wikipedia article
|, UOXP, URICASE, Urate oxidase, urate oxidase (pseudogene)|
Urate oxidase is mainly localised in the liver, where it forms a large electron-dense paracrystalline core in many peroxisomes. The enzyme exists as a tetramer of identical subunits, each containing a possible type 2 copper-binding site.
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.
Urate oxidase is the first 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.
Within the active site of urate oxidase, there is a catalytic site that holds uric acid and its analogues in the same orientation and a common catalytic site where oxygen, water, and hydrogen peroxide are sequentially driven. This mechanism is similar to that of catalase, which reverses hydrogen peroxide back to oxygen and also sequentially drives hydrogen peroxide and water through the common catalytic site. X-ray crystallography has shown that uric acid first binds to the active site as a monoanion, and is then deprotonated to a dianion. The dianion is stabilized by Arg 176 and Gln 228 of the enzyme. Oxygen will subsequently accept an electron pair from the uric acid dianion and be converted to hydrogen peroxide, which is replaced by water that performs a nucleophilic attack on the intermediate to produce 5-hydroxyisourate.
Significance of absence in humans
Of all animals that include meat in their diet, humans are the only animal unable to break down uric acid to allantoin. This is because humans do not have the necessary enzyme uricase. This leads to an increased possibility of an accumulation of uric acid in the body when animal products are eaten.
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, and so is absent in humans and other higher apes. 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.
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. Its presence provides the body with protection from oxidative damage, thus prolonging life and decreasing age-specific cancer rates.
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".
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. 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.
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.
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.
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.
- "Human PubMed Reference:".
- 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. PMID 3182808.
- 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. doi:10.1016/0014-5793(90)80789-L. PMID 2338140.
- 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. doi:10.1073/pnas.86.23.9412. PMC . PMID 2594778.
- 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.
- 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. PMID 18638417.
- 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.
- 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. doi:10.1371/journal.pone.0086651. PMID 24466188.
- 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.
- 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. PMID 1556746.
- 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. doi:10.1073/pnas.78.11.6858. PMC . PMID 6947260.
- "Pegloticase Drug Approval Package". US FDA. Retrieved 15 May 2017.
- 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): 1605. doi:10.1007/s00277-003-0608-2. PMID 12634948.
- 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. doi:10.1073/pnas.1010390107. PMC . PMID 20823251.
- 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.
- 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.
- 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. doi:10.1073/pnas.82.15.5040. PMC . PMID 16593585.
This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.
Uricase Provide feedback
No Pfam abstract.
Colloc'h N, el Hajji M, Bachet B, L'Hermite G, Schiltz M, Prange T, Castro B, Mornon JP; , Nat Struct Biol 1997;4:947-952.: Crystal structure of the protein drug urate oxidase-inhibitor complex at 2.05 A resolution. PUBMED:9360612 EPMC:9360612
External database links
This tab holds annotation information from the InterPro database.
InterPro entry IPR002042Uricase (EC) (urate oxidase) [PUBMED:3182808] is the peroxisomal enzyme responsible for the degradation of urate into allantoin:
Below is a listing of the unique domain organisations or architectures in which this domain is found. More...
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1Cannot generate PP/Heatmap alignments for seeds; no PP data available
Key: available, not generated, — not available.
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This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.
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|Seed source:||Pfam-B_1333 (release 3.0)|
|Author:||Bateman A , Griffiths-Jones SR|
|Number in seed:||276|
|Number in full:||3339|
|Average length of the domain:||134.50 aa|
|Average identity of full alignment:||24 %|
|Average coverage of the sequence by the domain:||86.72 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 45638612 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||18|
|Download:||download the raw HMM for this family|
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This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the More....
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How the sunburst is generated
The tree is built by considering the taxonomic lineage of each sequence that has a match to this family. For each node in the resulting tree, we draw an arc in the sunburst. The radius of the arc, its distance from the root node at the centre of the sunburst, shows the taxonomic level ("superkingdom", "kingdom", etc). The length of the arc represents either the number of sequences represented at a given level, or the number of species that are found beneath the node in the tree. The weighting scheme can be changed using the sunburst controls.
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Some species in the taxonomic tree may not have one or more of the main eight levels that we display. For example, Bos taurus is not assigned an order in the NCBI taxonomic tree. In such cases we mark the omitted level with, for example, "No order", in both the tooltip and the lineage summary.
Unmapped species names
The tree is built by looking at each sequence in the full alignment for the family. We take the name of the species given by UniProt and try to map that to the full taxonomic tree from NCBI. In some cases, the name chosen by UniProt does not map to any node in the NCBI tree, perhaps because the chosen name is listed as a synonym or a misspelling in the NCBI taxonomy.
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Since we reduce the species tree to only the eight main taxonomic levels, sequences that are mapped to the sub-species level in the tree would not normally be shown. Rather than leave out these species, we map them instead to their parent species. So, for example, for sequences belonging to one of the Vibrio cholerae sub-species in the NCBI taxonomy, we show them instead as belonging to the species Vibrio cholerae.
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The tree shows the occurrence of this domain across different species. More...
We show the species tree in one of two ways. For smaller trees we try to show an interactive representation, which allows you to select specific nodes in the tree and view them as an alignment or as a set of Pfam domain graphics.
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For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.
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Finally, we group sequences from the same organism according to the NCBI code that is assigned by UniProt, allowing us to count the number of distinct sequences on which the domain is found. This value is shown in the pink boxes.
We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.
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There is 1 interaction for this family. More...
We determine these interactions using iPfam, which considers the interactions between residues in three-dimensional protein structures and maps those interactions back to Pfam families. You can find more information about the iPfam algorithm in the journal article that accompanies the website.
For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the Uricase domain has been found. There are 340 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein sequence.
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