Summary: Uricase

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Wikipedia: Urate oxidase
Pfam
InterPro

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Urate oxidase Edit Wikipedia article

Urate oxidase, pseudogene

Identifiers

Symbols

UOX; UOXP; URICASE

External IDs

OMIM: 191540 HomoloGene: 7584 GeneCards: UOX Gene

EC number

1.7.3.3

Gene Ontology

Orthologs

Species

Human

Mouse

n/a

RefSeq (mRNA)

RefSeq (protein)

n/a

NP_033500

Location (UCSC)

Chr 1:
84.83 â 84.86 Mb

Chr 3:
146.25 â 146.3 Mb

PubMed search

[1]

[2]

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

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

Uric acid

5-hydroxyisourate

Allantoin

[edit] 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
PDBsum	structure summary

[edit] 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 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.

It has been proposed that the loss of urate oxidase protein 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".

[edit] 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]

[edit] References

^ Motojima K, Goto S, Kanaya S (1988). "Cloning and sequence analysis of cDNA for rat liver uricase". J. Biol. Chem. 263 (32): 16677â16681. 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): 156â158. doi:10.1016/0014-5793(90)80789-L. PMID 2338140.
^ ^a ^b 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): 9412â9416. doi:10.1073/pnas.86.23.9412. PMC 298506. PMID 2594778. //www.ncbi.nlm.nih.gov/pmc/articles/PMC298506/.
^ 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): 6858â62. doi:10.1073/pnas.78.11.6858. PMC 349151. PMID 6947260. //www.ncbi.nlm.nih.gov/pmc/articles/PMC349151/.
^ 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): 5040â5044. doi:10.1073/pnas.82.15.5040. PMC 390494. PMID 16593585. //www.ncbi.nlm.nih.gov/pmc/articles/PMC390494/.

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

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

B
enzm
1.1
- 2
- 3
- 4
- 5
- 6
- 7
- 8
- 10
- 11
- 13
- 14
- 15-18
2.1
- 2
- 3
- 4
- 5
- 6
- 7
- 8
2.7.10
2.7.11-12
3.1
- - 3.1.3.48
- 2
- 3
- 4
  - 3.4.21
- 5
- 6
- 7
- 22
- 23
- 24
4.1
- 2
- 3
- 4
- 5
- 6
5.1
- 2
- 3
- 4
- 99
6.1-3
- 4
- 5-6

Metabolism: amino acid metabolism Â· nucleotide enzymes

Purine metabolism

Anabolism	R5P->IMP: Ribose-phosphate diphosphokinase Â· Amidophosphoribosyltransferase Â· Phosphoribosylglycinamide formyltransferase Â· AIR synthetase (FGAM cyclase) Â· Phosphoribosylaminoimidazole carboxylase Â· Phosphoribosylaminoimidazolesuccinocarboxamide synthase Â· IMP synthase IMP->AMP: Adenylosuccinate synthase Â· Adenylosuccinate lyase Â· reverse (AMP deaminase) IMP->GMP: IMP dehydrogenase Â· GMP synthase Â· reverse (GMP reductase)

Nucleotide salvage	Hypoxanthine-guanine phosphoribosyltransferase Â· Adenine phosphoribosyltransferase

Catabolism	Adenosine deaminase Â· Purine nucleoside phosphorylase Â· Guanine deaminase Â· Xanthine oxidase Â· Urate oxidase

Pyrimidine metabolism

Anabolism	CAD (Carbamoyl phosphate synthase II, Aspartate carbamoyltransferase, Dihydroorotase) Dihydroorotate dehydrogenase Â· Orotidine 5'-phosphate decarboxylase/Uridine monophosphate synthetase CTP synthase

Catabolism	Dihydropyrimidine dehydrogenase Â· Dihydropyrimidinase/DPYS Â· Beta-ureidopropionase/UPB1

Deoxyribonucleotides

Ribonucleotide reductase Â· Nucleoside-diphosphate kinase Â· DCMP deaminase Â· Thymidylate synthase Â· Dihydrofolate reductase

M: MET

mt, k, c/g/r/p/y/i, f/h/s/l/o/e, a/u, n, m

k, cgrp/y/i, f/h/s/l/o/e, au, n, m, epon

m (A16/C10), i (k, c/g/r/p/y/i, f/h/s/o/e, a/u, n, m)

This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

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.

Literature references

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

HOMSTRAD:	Uricase
PANDIT:	PF01014
PROSITE:	PDOC00315
Pseudofam:	PF01014
SCOP:	1uox
SYSTERS:	Uricase

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: Urate + O₂ + H₂O = 5-hydroxyisourate + H₂O₂ Some species, like primates and birds, have lost the gene for uricase and are therefore unable to degrade urate [PUBMED:2594778]. Uricase is a protein of 300 to 400 amino acids, its sequence is well conserved. It is mainly localised in the liver, where it forms a large electron-dense paracrystalline core in many peroxisomes [PUBMED:2338140]. The enzyme exists as a tetramer of identical subunits, each containing a possible type 2 copper-binding site [PUBMED:2594778]. 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 [PUBMED:16593585].

Domain organisation

Below is a listing of the unique domain organisations or architectures in which this domain is found. More...

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Pfam Clan

This family is a member of clan THBO-biosyn (CL0334), which contains the following 6 members:

FolB GTP_cyclohydroI PTPS QueF QueF_N Uricase

Alignments

We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database using the family HMM. We also generate alignments using four representative proteomes (RP) sets, the NCBI sequence database, and our metagenomics sequence database. More...

There are various ways to view or download the sequence alignments that we store. We provide several sequence viewers and a plain-text Stockholm-format file for download.

Alignment types

We make a range of alignments for each Pfam-A family:

seed: the curated alignment from which the HMM for the family is built
full: the alignment generated by searching the sequence database using the HMM
RP15/RP35/RP55/RP75: Representative Proteomes (RPs) at 15%, 35%, 55% and 75% co-membership thresholds
NCBI: alignment generated by searching the NCBI sequence database using the family HMM
meta: alignment generated by searching the metagenomics sequence database using the family HMM

Viewing

You can see the alignments as HTML or in three different sequence viewers:

jalview: a Java applet developed at the University of Dundee. You will need Java installed before running jalview
HTML: an HTML page showing the whole alignment.Please note: full Pfam alignments can be very large. These HTML views are extremely large and often cause problems for browsers. Please use either jalview or the Pfam viewer if you have trouble viewing the HTML version
PP/Heatmap: an HTML-based representation of the alignment, coloured according to the posterior-probability (PP) values from the HMM. As for the standard HTML view, heatmap alignments can also be very large and slow to render.
Pfam viewer: an HTML-based viewer that uses DAS to retrieve alignment fragments on request

Reformatting

You can download (or view in your browser) a text representation of a Pfam alignment in various formats:

Selex
Stockholm
FASTA
MSF

You can also change the order in which sequences are listed in the alignment, change how insertions are represented, alter the characters that are used to represent gaps in sequences and, finally, choose whether to download the alignment or to view it in your browser directly.

Downloading

You may find that large alignments cause problems for the viewers and the reformatting tool, so we also provide all alignments in Stockholm format. You can download either the plain text alignment, or a gzipped version of it.

View options

We make a range of alignments for each Pfam-A family. You can see a description of each above. You can view these alignments in various ways but please note that some types of alignment are never generated while others may not be available for all families, most commonly because the alignments are too large to handle.

	Seed (122)	Full (880)	Representative proteomes				NCBI (906)	Meta (5)
	Seed (122)	Full (880)	RP15 (154)	RP35 (286)	RP55 (410)	RP75 (499)	NCBI (906)	Meta (5)
Jalview	View	View	View	View	View	View	View	View
HTML	View	View	View	View	View	View
PP/heatmap	₁	View	View	View	View	View
Pfam viewer	View	View

¹Cannot generate PP/Heatmap alignments for seeds; no PP data available

Key: available, not generated, — not available.

Format an alignment

	Seed (122)	Full (880)	Representative proteomes				NCBI (906)	Meta (5)
	Seed (122)	Full (880)	RP15 (154)	RP35 (286)	RP55 (410)	RP75 (499)	NCBI (906)	Meta (5)
Alignment:
Format:
Order:	Tree Alphabetical
Sequence:	Inserts lower case All upper case
Gaps:
Download/view:	Download View

Download options

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.

	Seed (122)	Full (880)	Representative proteomes				NCBI (906)	Meta (5)
	Seed (122)	Full (880)	RP15 (154)	RP35 (286)	RP55 (410)	RP75 (499)	NCBI (906)	Meta (5)
Raw Stockholm	Download	Download	Download	Download	Download	Download	Download	Download
Gzipped	Download	Download	Download	Download	Download	Download	Download	Download

You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

External links

MyHits provides a collection of tools to handle multiple sequence alignments. For example, one can refine a seed alignment (sequence addition or removal, re-alignment or manual edition) and then search databases for remote homologs using HMMER3.

HMM logo

HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...

Trees

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.

Note: You can also download the data file for the tree.

Curation and family details

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.

Curation

Seed source:

Pfam-B_1333 (release 3.0)

Previous IDs:

none

Type:

Domain

Author:

Bateman A, Griffiths-Jones SR

Number in seed:

122

Number in full:

880

Average length of the domain:

136.40 aa

Average identity of full alignment:

24 %

Average coverage of the sequence by the domain:

88.46 %

HMM information

HMM build commands:

build method: hmmbuild -o /dev/null HMM SEED

search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq

Model details:

Parameter	Sequence	Domain
Gathering cut-off	25.0	25.0
Trusted cut-off	26.0	25.8
Noise cut-off	24.3	23.9

Model length:

138

Family (HMM) version:

13

Download:

download the raw HMM for this family

Species distribution

Sunburst
Tree

Sunburst controls

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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 adjacent tab. More...

This chart is a modified "sunburst" visualisation of the species tree for this family. It shows each node in the tree as a separate arc, arranged radially with the superkingdoms at the centre and the species arrayed around the outermost ring.

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:

superkingdom
kingdom
phylum
class
order
family
genus
species

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.

As you move your mouse across the sunburst, the current node will be highlighted. In the top section of the controls panel we show a summary of the lineage of the currently highlighed node. If you pause over an arc, a tooltip will be shown, giving the name of the taxonomic level in the title and a summary of the number of sequences and species below that node in the tree.

Anomalies in the taxonomy tree

There are some situations that the sunburst tree cannot easily handle and for which we have work-arounds in place.

Missing taxonomic levels

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".

Sub-species

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

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Species trees

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.

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Interactive tree

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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Interactions

There is 1 interaction for this family. More...

Uricase

Structures

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 220 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 seqence.

Loading structure mapping...

Archea	Eukaryota
Bacteria	Other sequences
Viruses	Unclassified
Viroids	Unclassified sequence

Family: Uricase (PF01014)

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Summary: Uricase

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Urate oxidase Edit Wikipedia article

Contents

[edit] Structure

[edit] Significance of absence in humans

[edit] In legumes

[edit] References

Uricase Provide feedback

Literature references

External database links

InterPro entry IPR002042

Domain organisation

Pfam Clan

Alignments

Alignment types

Viewing

Reformatting

Downloading

View options

Format an alignment

Download options

External links

HMM logo

Trees

Curation and family details

Curation

HMM information

Species distribution

Sunburst controls

Weight segments by...

Change the size of the sunburst

Colour assignments

Selections

Currently selected:

How the sunburst is generated

Colouring and labels

Anomalies in the taxonomy tree

Missing taxonomic levels

Unmapped species names

Sub-species

Too many species/sequences

Tree controls

Annotation

Download tree

Selected sequences

Species trees

Interactive tree

Interactions

Structures