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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
Urate oxidase is found in nearly all organisms, from bacteria to mammals, but is inactive in humans and several other great apes, having been lost in primate evolution. 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.
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.
However, uric acid plays a complex physiological role in several processes, including inflammation and danger signalling, and modern purine-rich diets can lead to hyperuricaemia, which is linked to many diseases including an increased risk of developing 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, 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:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- 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): 16677â€“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): 156â€“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): 9412â€“6. doi:10.1073/pnas.86.23.9412. PMC 298506. 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): 144â€“8. doi:10.1038/nchembio768. PMID 16462750.
- Gabison L, PrangÃ© 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.
- Colloc'h N, el Hajji M, Bachet B, L'Hermite G, Schiltz M, PrangÃ© 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): 947â€“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. PMC 3900588. PMID 24466188.
- Estarellas C, Frontera A, QuiÃ±onero D, DeyÃ PM (January 2011). "Relevant anion-Ï€ interactions in biological systems: the case of urate oxidase". Angewandte Chemie. 50 (2): 415â€“8. doi:10.1002/anie.201005635. PMID 21132687.
- So A, Thorens B (June 2010). "Uric acid transport and disease". The Journal of Clinical Investigation. 120 (6): 1791â€“9. doi:10.1172/JCI42344. PMC 2877959. PMID 20516647.
- 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): 78â€“84. doi:10.1007/BF00163854. 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): 6858â€“62. doi:10.1073/pnas.78.11.6858. PMC 349151. PMID 6947260.
- 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): 160â€“6. doi:10.1007/s11926-011-0162-1. PMC 3093438. PMID 21234729.
- "Pegloticase Drug Approval Package". US FDA. Retrieved 15 May 2017.
- WÃ¶ssmann 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): 160â€“5. 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): 16625â€“30. doi:10.1073/pnas.1010390107. PMC 2944704. 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): e146â€“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): 730â€“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): 5040â€“4. doi:10.1073/pnas.82.15.5040. PMC 390494. 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
Internal database links
External database links
This tab holds annotation information from the InterPro database.
InterPro entry IPR002042
Uricase (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...
The graphic that is shown by default represents the longest sequence with a given architecture. Each row contains the following information:
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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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We make all of our alignments available in Stockholm format. You can download them here as raw, plain text files or as gzip-compressed files.
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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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This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.
|Seed source:||Pfam-B_1333 (release 3.0)|
|Author:||Bateman A , Griffiths-Jones SR|
|Number in seed:||265|
|Number in full:||3906|
|Average length of the domain:||134.20 aa|
|Average identity of full alignment:||24 %|
|Average coverage of the sequence by the domain:||86.58 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 47079205 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||19|
|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.
In order to reduce the complexity of the representation, we reduce the number of taxonomic levels that we show. We consider only the following eight major taxonomic levels:
Colouring and labels
Segments of the tree are coloured approximately according to their superkingdom. For example, archeal branches are coloured with shades of orange, eukaryotes in shades of purple, etc. The colour assignments are shown under the sunburst controls. Where space allows, the name of the taxonomic level will be written on the arc itself.
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There are some situations that the sunburst tree cannot easily handle and for which we have work-arounds in place.
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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.
So that these nodes are not simply omitted from the sunburst tree, we group them together in a separate branch (or segment of the sunburst tree). Since we cannot determine the lineage for these unmapped species, we show all levels between the superkingdom and the species as "uncategorised".
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.
Too many species/sequences
For large species trees, you may see blank regions in the outer layers of the sunburst. These occur when there are large numbers of arcs to be drawn in a small space. If an arc is less than approximately one pixel wide, it will not be drawn and the space will be left blank. You may still be able to get some information about the species in that region by moving your mouse across the area, but since each arc will be very small, it will be difficult to accurately locate a particular species.
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.
Unfortunately we have found that there are problems viewing the interactive tree when the it becomes larger than a certain limit. Furthermore, we have found that Internet Explorer can become unresponsive when viewing some trees, regardless of their size. We therefore show a text representation of the species tree when the size is above a certain limit or if you are using Internet Explorer to view the site.
If you are using IE you can still load the interactive tree by clicking the "Generate interactive tree" button, but please be aware of the potential problems that the interactive species tree can cause.
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.
We also count the number of unique sequences on which each domain is found, which is shown in green. Note that a domain may appear multiple times on the same sequence, leading to the difference between these two numbers.
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 394 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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