Urate oxidase: Difference between revisions

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{{Short description|Pseudogene in the species Homo sapiens}}
{{Short description|Pseudogene in the species Homo sapiens}}
{{Infobox_gene}}
{{cs1 config|name-list-style=vanc|display-authors=6}}
{{Infobox gene}}


The enzyme '''urate oxidase''' ('''UO'''), '''uricase''' or '''factor-independent urate hydroxylase''', absent in humans, catalyzes the [[oxidation]] of [[uric acid]] to [[5-hydroxyisourate]]:<ref name="PUB00002471">{{cite journal | vauthors = Motojima K, Kanaya S, Goto S | title = Cloning and sequence analysis of cDNA for rat liver uricase | journal = The Journal of Biological Chemistry | volume = 263 | issue = 32 | pages = 16677–81 | date = November 1988 | doi = 10.1016/S0021-9258(18)37443-X | pmid = 3182808 | doi-access = free }}</ref>
The enzyme '''urate oxidase''' ('''UO'''), also known as '''uricase''' or '''factor-independent urate hydroxylase''', is found in nearly all species from bacteria to mammals, but is not expressed in humans, [[great ape]]s, and certain [[New World monkey]]s, in which it exists as a [[pseudogene]]. It catalyzes the [[oxidation]] of [[uric acid]] to [[5-hydroxyisourate]]:<ref name="Motojima_1988">{{cite journal | vauthors = Motojima K, Kanaya S, Goto S | title = Cloning and sequence analysis of cDNA for rat liver uricase | journal = The Journal of Biological Chemistry | volume = 263 | issue = 32 | pages = 16677–16681 | date = November 1988 | pmid = 3182808 | doi = 10.1016/S0021-9258(18)37443-X | doi-access = free }}</ref>


:[[Uric acid]] + O<sub>2</sub> + H<sub>2</sub>O → [[5-hydroxyisourate]] + [[hydrogen peroxide|H<sub>2</sub>O<sub>2</sub>]]
:[[Uric acid]] + O<sub>2</sub> + H<sub>2</sub>O → [[5-hydroxyisourate]] + [[hydrogen peroxide|H<sub>2</sub>O<sub>2</sub>]]
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[[File:UreateOxidaseRxn.svg|thumb|left|602px|sequence of oxidation of ureate.]]
[[File:UreateOxidaseRxn.svg|thumb|left|602px|sequence of oxidation of ureate.]]


== Structure ==
== Species distribution ==
Urate oxidase is found in nearly all organisms, from [[bacteria]] to [[mammals]], but is a [[pseudogene]] in humans, [[great ape]]s, and certain [[New World monkey]]s, having been lost during [[primate]] [[evolution]].<ref name="Wu_1989" />  This means that instead of producing [[allantoin]] as the end product of [[purine]] oxidation, the pathway ends with uric acid. This leads to humans and many primates having much higher and more highly variable levels of urate in the blood than most other mammals.<ref name="Uric acid transport and disease">{{cite journal | vauthors = So A, Thorens B | title = Uric acid transport and disease | journal = The Journal of Clinical Investigation | volume = 120 | issue = 6 | pages = 1791–1799 | date = June 2010 | pmid = 20516647 | pmc = 2877959 | doi = 10.1172/JCI42344 }}</ref>
 
== Convergent evolution ==
Urate oxidase is a notable example of the existence of [[non-homologous isofunctional enzymes]], proteins with independent evolutionary origin catalyzing the same [[chemical reaction]].
 
Besides the cofactorless urate oxidase (UOX), which is found in all three [[Domain (biology)|domains]] of life, other bacterial proteins are known that catalyze the same reaction without being evolutionarily related to UOX. These are two different oxidases (named HpxO and HpyO) that use [[FAD]] and [[NAD+]] as [[cofactor (biochemistry)|cofactors]], and one [[integral membrane protein]] (named PuuD) that additionally contains a [[cytochrome c]] protein domain.<ref name="Doniselli_2015">{{Cite journal | vauthors = Doniselli N, Monzeglio E, Dal Palù A, Merli A, Percudani R | title = The identification of an integral membrane, cytochrome c urate oxidase completes the catalytic repertoire of a therapeutic enzyme | journal = Scientific Reports | volume = 5 | page = 13798 | date = 2015 | pmid = 26349049 | pmc = 4562309 | doi = 10.1038/srep13798 | article-number = 13798 | bibcode = 2015NatSR...513798D }}</ref>
 
== Localization ==


Urate oxidase is mainly localised in the liver, where it forms a large electron-dense paracrystalline core in many [[peroxisome]]s.<ref name="PUB00001587">{{cite journal | vauthors = Motojima K, Goto S | title = Organization of rat uricase chromosomal gene differs greatly from that of the corresponding plant gene | journal = FEBS Letters | volume = 264 | issue = 1 | pages = 156–8 | date = May 1990 | pmid = 2338140 | doi = 10.1016/0014-5793(90)80789-L | bibcode = 1990FEBSL.264..156M | s2cid = 36132942 }}</ref> The enzyme exists as a tetramer of identical subunits, each containing a possible type 2 copper-binding site.<ref name="PUB00004693">{{cite journal|vauthors=Wu XW, Lee CC, Muzny DM, Caskey CT|date=December 1989|title=Urate oxidase: primary structure and evolutionary implications|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=86|issue=23|pages=9412–6|doi=10.1073/pnas.86.23.9412|pmc=298506|pmid=2594778|bibcode=1989PNAS...86.9412W|doi-access=free}}</ref>
Urate oxidase is mainly localised in the liver, where it forms a large electron-dense paracrystalline core in many [[peroxisome]]s.<ref name="Motojima_1990">{{cite journal | vauthors = Motojima K, Goto S | title = Organization of rat uricase chromosomal gene differs greatly from that of the corresponding plant gene | journal = FEBS Letters | volume = 264 | issue = 1 | pages = 156–158 | date = May 1990 | pmid = 2338140 | doi = 10.1016/0014-5793(90)80789-L | bibcode = 1990FEBSL.264..156M | s2cid = 36132942 }}</ref>


Urate oxidase is a [[tetrameric protein|homotetrameric]] enzyme containing four identical active sites situated at the interfaces between its four subunits. UO from ''[[Aspergillus flavus|A. flavus]]'' is made up of 301 residues and has a molecular weight of 33438 [[dalton (unit)|daltons]]. It is unique among the [[oxidase]]s 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.
== Structure ==


{|
{{Infobox protein family
|- valign="top"
| {{infobox enzyme
| Name      = factor-independent urate hydroxylase
| EC_number  = 1.7.3.3
| CAS_number = 9002-12-4
| GO_code    = 0004846
| image      =
| width      =
| caption    = 
}}
| {{Infobox protein family
| Symbol = Uricase  
| Symbol = Uricase  
| Name = Uricase  
| Name = Uricase  
Line 42: Line 40:
| OPM protein=  
| OPM protein=  
| PDB= {{PDB3|1ws2}}D:142-291  {{PDB3|1r56}}A:142-291  {{PDB3|1ws3}}B:142-291 {{PDB3|1xxj}}D:142-291  {{PDB3|1xt4}}A:142-291  {{PDB3|1r4u}}A:142-291 {{PDB3|1r51}}A:142-291  {{PDB3|1r4s}}A:142-291  {{PDB3|1j2g}}B:336-476   
| PDB= {{PDB3|1ws2}}D:142-291  {{PDB3|1r56}}A:142-291  {{PDB3|1ws3}}B:142-291 {{PDB3|1xxj}}D:142-291  {{PDB3|1xt4}}A:142-291  {{PDB3|1r4u}}A:142-291 {{PDB3|1r51}}A:142-291  {{PDB3|1r4s}}A:142-291  {{PDB3|1j2g}}B:336-476   
}}
}}
|}


== Reaction mechanism ==
The enzyme exists as a tetramer of identical subunits, each containing a possible type 2 copper-binding site.<ref name="Wu_1989">{{cite journal | vauthors = Wu XW, Lee CC, Muzny DM, Caskey CT | title = Urate oxidase: primary structure and evolutionary implications | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 86 | issue = 23 | pages = 9412–9416 | date = December 1989 | pmid = 2594778 | pmc = 298506 | doi = 10.1073/pnas.86.23.9412 | bibcode = 1989PNAS...86.9412W | doi-access = free }}</ref>
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 mixture|racemic]] allantoin.<ref>{{cite journal | vauthors = Ramazzina I, Folli C, Secchi A, Berni R, Percudani R | title = Completing the uric acid degradation pathway through phylogenetic comparison of whole genomes | language = En | journal = Nature Chemical Biology | volume = 2 | issue = 3 | pages = 144–8 | date = March 2006 | pmid = 16462750 | doi = 10.1038/nchembio768 | s2cid = 13441301 }}</ref>


The active site binds uric acid (and its analogues), allowing it to interact with O<sub>2</sub>.<ref>{{cite journal | vauthors = Gabison L, Prangé T, Colloc'h N, El Hajji M, Castro B, Chiadmi M | title = Structural analysis of urate oxidase in complex with its natural substrate inhibited by cyanide: mechanistic implications | journal = BMC Structural Biology | volume = 8 | pages = 32 | date = July 2008 | pmid = 18638417 | pmc = 2490695 | doi = 10.1186/1472-6807-8-32 | doi-access = free }}</ref> 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  [[Arginine|Arg]] 176 and [[Glutamine|Gln]] 228 .<ref>{{cite journal | vauthors = Colloc'h N, el Hajji M, Bachet B, L'Hermite G, Schiltz M, Prangé T, Castro B, Mornon JP | title = Crystal structure of the protein drug urate oxidase-inhibitor complex at 2.05 A resolution | language = En | journal = Nature Structural Biology | volume = 4 | issue = 11 | pages = 947–52 | date = November 1997 | pmid = 9360612 | doi = 10.1038/nsb1197-947 | s2cid = 1282767 | url = http://infoscience.epfl.ch/record/83588 }}</ref> 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.<ref>{{cite journal | vauthors = Oksanen E, Blakeley MP, El-Hajji M, Ryde U, Budayova-Spano M | title = The Neutron Structure of Urate Oxidase Resolves a Long-Standing Mechanistic Conundrum and Reveals Unexpected Changes in Protonation | journal = PLOS ONE | volume = 9 | issue = 1 | pages = e86651 | date = 2014-01-23 | pmid = 24466188 | pmc = 3900588 | doi = 10.1371/journal.pone.0086651 | bibcode = 2014PLoSO...986651O | doi-access = free }}</ref>
Urate oxidase is a [[tetrameric protein|homotetrameric]] enzyme containing four identical active sites situated at the interfaces between its four subunits. UO from ''[[Aspergillus flavus|A. flavus]]'' is made up of 301 residues and has a molecular weight of 33438 [[dalton (unit)|daltons]]. It is unique among the [[oxidase]]s 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 known to be inhibited by both [[cyanide]] and [[chloride]] ions. Inhibition involves anion-π interactions between the inhibitor and the uric acid substrate.<ref>{{cite journal | vauthors = Estarellas C, Frontera A, Quiñonero D, Deyà PM | title = Relevant anion-π interactions in biological systems: the case of urate oxidase | journal = Angewandte Chemie | volume = 50 | issue = 2 | pages = 415–8 | date = January 2011 | pmid = 21132687 | doi = 10.1002/anie.201005635 }}</ref>
== Function ==
{{infobox enzyme
| Name      = factor-independent urate hydroxylase
| EC_number  = 1.7.3.3
| CAS_number = 9002-12-4
| GO_code    = 0004846
| image      =
| width      =
| caption    = 
}}
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 mixture|racemic]] allantoin.<ref>{{cite journal | vauthors = Ramazzina I, Folli C, Secchi A, Berni R, Percudani R | title = Completing the uric acid degradation pathway through phylogenetic comparison of whole genomes | journal = Nature Chemical Biology | volume = 2 | issue = 3 | pages = 144–148 | date = March 2006 | pmid = 16462750 | doi = 10.1038/nchembio768 | bibcode = 2006NatCB...2..144R | language = En | s2cid = 13441301 }}</ref>
 
The active site binds uric acid (and its analogues), allowing it to interact with O<sub>2</sub>.<ref>{{cite journal | vauthors = Gabison L, Prangé T, Colloc'h N, El Hajji M, Castro B, Chiadmi M | title = Structural analysis of urate oxidase in complex with its natural substrate inhibited by cyanide: mechanistic implications | journal = BMC Structural Biology | volume = 8 | page = 32 | date = July 2008 | pmid = 18638417 | pmc = 2490695 | doi = 10.1186/1472-6807-8-32 | article-number = 32 | doi-access = free }}</ref> 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  [[Arginine|Arg]] 176 and [[Glutamine|Gln]] 228 .<ref>{{cite journal | vauthors = Colloc'h N, el Hajji M, Bachet B, L'Hermite G, Schiltz M, Prangé T, Castro B, Mornon JP | title = Crystal structure of the protein drug urate oxidase-inhibitor complex at 2.05 A resolution | journal = Nature Structural Biology | volume = 4 | issue = 11 | pages = 947–952 | date = November 1997 | pmid = 9360612 | doi = 10.1038/nsb1197-947 | language = En | s2cid = 1282767 | url = http://infoscience.epfl.ch/record/83588 }}</ref> 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.<ref>{{cite journal | vauthors = Oksanen E, Blakeley MP, El-Hajji M, Ryde U, Budayova-Spano M | title = The Neutron Structure of Urate Oxidase Resolves a Long-Standing Mechanistic Conundrum and Reveals Unexpected Changes in Protonation | journal = PLOS ONE | volume = 9 | issue = 1 | article-number = e86651 | date = 2014-01-23 | pmid = 24466188 | pmc = 3900588 | doi = 10.1371/journal.pone.0086651 | bibcode = 2014PLoSO...986651O | doi-access = free }}</ref>


==Significance of absence in humans==
== Inhibitors ==
Urate oxidase is found in nearly all organisms, from [[bacteria]] to [[mammals]], but is [[Pseudogene|inactive]] in humans and all apes (great and lesser apes), having been lost in [[hominoid]] ancestors during [[primate]] [[evolution]].<ref name="PUB00004693" />  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.<ref name="Uric acid transport and disease">{{cite journal | vauthors = So A, Thorens B | title = Uric acid transport and disease | journal = The Journal of Clinical Investigation | volume = 120 | issue = 6 | pages = 1791–9 | date = June 2010 | pmid = 20516647 | pmc = 2877959 | doi = 10.1172/JCI42344 }}</ref>
 
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.<ref>{{cite journal | vauthors = Estarellas C, Frontera A, Quiñonero D, Deyà PM | title = Relevant anion-π interactions in biological systems: the case of urate oxidase | journal = Angewandte Chemie | location = International Ed. in English | volume = 50 | issue = 2 | pages = 415–418 | date = January 2011 | pmid = 21132687 | doi = 10.1002/anie.201005635 | bibcode = 2011ACIE...50..415E }}</ref>
 
== Clinical significance ==


Genetically, the loss of urate oxidase function in humans was caused by two [[nonsense mutation]]s at codons 33 and 187 and an aberrant splice site.<ref>{{cite journal | vauthors = Wu XW, Muzny DM, Lee CC, Caskey CT | title = Two independent mutational events in the loss of urate oxidase during hominoid evolution | journal = Journal of Molecular Evolution | volume = 34 | issue = 1 | pages = 78–84 | date = January 1992 | pmid = 1556746 | doi = 10.1007/BF00163854 | bibcode = 1992JMolE..34...78W | s2cid = 33424555 }}</ref>
Genetically, the loss of urate oxidase function in humans was caused by two [[nonsense mutation]]s at codons 33 and 187 and an aberrant splice site.<ref>{{cite journal | vauthors = Wu XW, Muzny DM, Lee CC, Caskey CT | title = Two independent mutational events in the loss of urate oxidase during hominoid evolution | journal = Journal of Molecular Evolution | volume = 34 | issue = 1 | pages = 78–84 | date = January 1992 | pmid = 1556746 | doi = 10.1007/BF00163854 | bibcode = 1992JMolE..34...78W | s2cid = 33424555 }}</ref>


It has been proposed that the loss of urate oxidase [[gene expression]] has been advantageous to [[hominoid]]s, since uric acid is a powerful [[antioxidant]] and scavenger of singlet oxygen and [[Radical (chemistry)|radical]]s.  Its presence provides the body with protection from [[oxidative]] damage, thus prolonging life and decreasing age-specific cancer rates.<ref name="pmid6947260">{{cite journal | vauthors = Ames BN, Cathcart R, Schwiers E, Hochstein P | title = Uric acid provides an antioxidant defense in humans against oxidant- and radical-caused aging and cancer: a hypothesis | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 78 | issue = 11 | pages = 6858–62 | date = November 1981 | pmid = 6947260 | pmc = 349151 | doi = 10.1073/pnas.78.11.6858 | bibcode = 1981PNAS...78.6858A | doi-access = free }}</ref>
It has been proposed that the loss of urate oxidase [[gene expression]] has been advantageous to [[hominoid]]s, since uric acid is a powerful [[antioxidant]] and scavenger of singlet oxygen and [[Radical (chemistry)|radical]]s.  Its presence provides the body with protection from [[oxidative]] damage, thus prolonging life and decreasing age-specific cancer rates.<ref name="Ames_1981">{{cite journal | vauthors = Ames BN, Cathcart R, Schwiers E, Hochstein P | title = Uric acid provides an antioxidant defense in humans against oxidant- and radical-caused aging and cancer: a hypothesis | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 78 | issue = 11 | pages = 6858–6862 | date = November 1981 | pmid = 6947260 | pmc = 349151 | doi = 10.1073/pnas.78.11.6858 | bibcode = 1981PNAS...78.6858A | doi-access = free }}</ref>


However, uric acid plays a complex physiological role in several processes, including [[inflammation]] and danger signalling,<ref>{{cite journal | vauthors = Ghaemi-Oskouie F, Shi Y | title = The role of uric acid as an endogenous danger signal in immunity and inflammation | journal = Current Rheumatology Reports | volume = 13 | issue = 2 | pages = 160–6 | date = April 2011 | pmid = 21234729 | pmc = 3093438 | doi = 10.1007/s11926-011-0162-1 }}</ref> and modern purine-rich diets can lead to [[Hyperuricemia|hyperuricaemia]], which is linked to many diseases including an increased risk of developing [[gout]].<ref name="Uric acid transport and disease"/>
However, uric acid plays a complex physiological role in several processes, including [[inflammation]] and danger signalling,<ref>{{cite journal | vauthors = Ghaemi-Oskouie F, Shi Y | title = The role of uric acid as an endogenous danger signal in immunity and inflammation | journal = Current Rheumatology Reports | volume = 13 | issue = 2 | pages = 160–166 | date = April 2011 | pmid = 21234729 | pmc = 3093438 | doi = 10.1007/s11926-011-0162-1 }}</ref> and modern purine-rich diets can lead to [[Hyperuricemia|hyperuricaemia]], which is linked to many diseases including an increased risk of developing [[gout]].<ref name="Uric acid transport and disease"/>


== Medical uses ==
Children with [[Non-Hodgkin lymphoma|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 [[Nephron|renal tubules]] and [[Collecting duct system|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.<ref>{{cite journal | vauthors = Wössmann W, Schrappe M, Meyer U, Zimmermann M, Reiter A | title = Incidence of tumor lysis syndrome in children with advanced stage Burkitt's lymphoma/leukemia before and after introduction of prophylactic use of urate oxidase | journal = Annals of Hematology | volume = 82 | issue = 3 | pages = 160–165 | date = March 2003 | pmid = 12634948 | doi = 10.1007/s00277-003-0608-2 | s2cid = 27279071 }}</ref> 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.<ref>{{cite journal | vauthors = 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 | title = Deficiency of 5-hydroxyisourate hydrolase causes hepatomegaly and hepatocellular carcinoma in mice | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 107 | issue = 38 | pages = 16625–16630 | date = September 2010 | pmid = 20823251 | pmc = 2944704 | doi = 10.1073/pnas.1010390107 | bibcode = 2010PNAS..10716625S | doi-access = free }}</ref>
{{More medical citations needed|section|date=March 2018}}
Urate oxidase is formulated as a protein drug ([[rasburicase]]) for the treatment of acute [[hyperuricemia]] in patients receiving [[chemotherapy]]. A [[PEGylation|PEGylated]] form of urate oxidase, [[pegloticase]], was FDA approved in 2010 for the treatment of chronic gout in adult patients refractory to "conventional therapy".<ref>{{cite web|title=Pegloticase Drug Approval Package|url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/125293s0000TOC.cfm|archive-url=https://web.archive.org/web/20210227045114/https://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/125293s0000TOC.cfm|url-status=dead|archive-date=February 27, 2021|publisher=US FDA|access-date=15 May 2017}}</ref>


== Disease relevance ==
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.<ref>{{cite journal | vauthors = Thyrion L, Portelli J, Raedt R, Glorieux G, Larsen LE, Sprengers M, Van Lysebettens W, Carrette E, Delbeke J, Vonck K, Boon P | title = Disruption, but not overexpression of urate oxidase alters susceptibility to pentylenetetrazole- and pilocarpine-induced seizures in mice | journal = Epilepsia | volume = 57 | issue = 7 | pages = e146–e150 | date = July 2016 | pmid = 27158916 | doi = 10.1111/epi.13410 | doi-access = free }}</ref>
{{More medical citations needed|section|date=March 2018}}
Children with [[Non-Hodgkin lymphoma|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 [[Nephron|renal tubules]] and [[Collecting duct system|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.<ref>{{cite journal | vauthors = Wössmann W, Schrappe M, Meyer U, Zimmermann M, Reiter A | title = Incidence of tumor lysis syndrome in children with advanced stage Burkitt's lymphoma/leukemia before and after introduction of prophylactic use of urate oxidase | journal = Annals of Hematology | volume = 82 | issue = 3 | pages = 160–5 | date = March 2003 | pmid = 12634948 | doi = 10.1007/s00277-003-0608-2 | s2cid = 27279071 }}</ref> 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.<ref>{{cite journal | vauthors = 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 | title = Deficiency of 5-hydroxyisourate hydrolase causes hepatomegaly and hepatocellular carcinoma in mice | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 107 | issue = 38 | pages = 16625–30 | date = September 2010 | pmid = 20823251 | doi = 10.1073/pnas.1010390107 | pmc = 2944704 | bibcode = 2010PNAS..10716625S | doi-access = free }}</ref>


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.<ref>{{cite journal | vauthors = Thyrion L, Portelli J, Raedt R, Glorieux G, Larsen LE, Sprengers M, Van Lysebettens W, Carrette E, Delbeke J, Vonck K, Boon P | title = Disruption, but not overexpression of urate oxidase alters susceptibility to pentylenetetrazole- and pilocarpine-induced seizures in mice | journal = Epilepsia | volume = 57 | issue = 7 | pages = e146-50 | date = July 2016 | pmid = 27158916 | doi = 10.1111/epi.13410 | doi-access = free }}</ref>
[[Graft-versus-host disease]] (GVHD) is often a side effect of allogeneic [[hematopoietic stem cell transplantation]] (HSCT), driven by donor [[T cell]]s 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.<ref>{{cite journal | vauthors = Yeh AC, Brunner AM, Spitzer TR, Chen YB, Coughlin E, McAfee S, Ballen K, Attar E, Caron M, Preffer FI, Yeap BY, Dey BR | title = Phase I study of urate oxidase in the reduction of acute graft-versus-host disease after myeloablative allogeneic stem cell transplantation | journal = Biology of Blood and Marrow Transplantation| volume = 20 | issue = 5 | pages = 730–734 | date = May 2014 | pmid = 24530972 | doi = 10.1016/j.bbmt.2014.02.003 | doi-access = free }}</ref>


[[Graft-versus-host disease]] (GVHD) is often a side effect of allogeneic [[hematopoietic stem cell transplantation]] (HSCT), driven by donor [[T cell]]s 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.<ref>{{cite journal | vauthors = Yeh AC, Brunner AM, Spitzer TR, Chen YB, Coughlin E, McAfee S, Ballen K, Attar E, Caron M, Preffer FI, Yeap BY, Dey BR | title = Phase I study of urate oxidase in the reduction of acute graft-versus-host disease after myeloablative allogeneic stem cell transplantation | journal = Biology of Blood and Marrow Transplantation | volume = 20 | issue = 5 | pages = 730–4 | date = May 2014 | pmid = 24530972 | doi = 10.1016/j.bbmt.2014.02.003 | doi-access = free }}</ref>
== Medical uses ==
{{More medical citations needed|section|date=March 2018}}
Urate oxidase is formulated as a protein drug ([[rasburicase]]) for the treatment of acute [[hyperuricemia]] in patients receiving [[chemotherapy]]. A [[PEGylation|PEGylated]] form of urate oxidase, [[pegloticase]], was FDA approved in 2010 for the treatment of chronic gout in adult patients refractory to "conventional therapy".<ref>{{cite web | title = Pegloticase Drug Approval Package | url = https://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/125293s0000TOC.cfm | archive-url = https://web.archive.org/web/20210227045114/https://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/125293s0000TOC.cfm | archive-date = February 27, 2021 | publisher = US FDA | access-date = 15 May 2017 }}</ref>


==In legumes==
==In legumes==
UO is also an essential enzyme in the ureide pathway, where [[nitrogen fixation]] occurs in the root nodules of [[legume]]s. The fixed nitrogen is converted to [[metabolite]]s that are transported from the roots throughout the plant to provide the needed nitrogen for [[amino acid]] biosynthesis.
UO is also an essential enzyme in the ureide pathway, where [[nitrogen fixation]] occurs in the root nodules of [[legume]]s. The fixed nitrogen is converted to [[metabolite]]s 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.<ref name="PUB00004611">{{cite journal | vauthors = Nguyen T, Zelechowska M, Foster V, Bergmann H, Verma DP | title = Primary structure of the soybean nodulin-35 gene encoding uricase II localized in the peroxisomes of uninfected cells of nodules | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 82 | issue = 15 | pages = 5040–4 | date = August 1985 | pmid = 16593585 | pmc = 390494 | doi = 10.1073/pnas.82.15.5040 | bibcode = 1985PNAS...82.5040N | doi-access = free }}</ref>
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.<ref name="Nguyen_1985">{{cite journal | vauthors = Nguyen T, Zelechowska M, Foster V, Bergmann H, Verma DP | title = Primary structure of the soybean nodulin-35 gene encoding uricase II localized in the peroxisomes of uninfected cells of nodules | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 82 | issue = 15 | pages = 5040–5044 | date = August 1985 | pmid = 16593585 | pmc = 390494 | doi = 10.1073/pnas.82.15.5040 | bibcode = 1985PNAS...82.5040N | doi-access = free }}</ref>
 
== Convergent evolution ==
Urate oxidase is a notable example of the existence of [[non-homologous isofunctional enzymes]], proteins with independent evolutionary origin catalyzing the same [[chemical reaction]].
 
Besides the cofactorless urate oxidase (UOX), which is found in all three [[Domain (biology)|domains]] of life, other bacterial proteins are known that catalyze the same reaction without being evolutionarily related to UOX. These are two different oxidases (named HpxO and HpyO) that use [[FAD]] and [[NAD+]] as [[cofactor (biochemistry)|cofactors]], and one [[integral membrane protein]] (named PuuD) that additionally contains a [[cytochrome c]] protein domain.<ref name="PMC4562309"> {{Cite journal| doi = 10.1038/srep13798| volume = 5| last1 = Doniselli| first1 = N.| last2 = Monzeglio| first2 = E.| last3 = Dal Palù| first3 = A.| last4 = Merli| first4 = A.| last5 = Percudani| first5 = R.| title = The identification of an integral membrane, cytochrome c urate oxidase completes the catalytic repertoire of a therapeutic enzyme| journal = Scientific Reports| date = 2015| page = 13798| pmid = 26349049| pmc = 4562309| bibcode = 2015NatSR...513798D}}</ref>


== See also ==
== See also ==

Latest revision as of 06:43, 3 December 2025

Template:Short description Template:Cs1 config Template:Infobox gene

The enzyme urate oxidase (UO), also known as uricase or factor-independent urate hydroxylase, is found in nearly all species from bacteria to mammals, but is not expressed in humans, great apes, and certain New World monkeys, in which it exists as a pseudogene. It catalyzes the oxidation of uric acid to 5-hydroxyisourate:[1]

Uric acid + O2 + H2O → 5-hydroxyisourate + H2O2
5-hydroxyisourate + H2O → 2-oxo-4-hydroxy-4-carboxy-5-ureidoimidazoline
2-oxo-4-hydroxy-4-carboxy-5-ureidoimidazoline → allantoin + CO2
File:UreateOxidaseRxn.svg
sequence of oxidation of ureate.

Species distribution

Urate oxidase is found in nearly all organisms, from bacteria to mammals, but is a pseudogene in humans, great apes, and certain New World monkeys, having been lost during primate evolution.[2] This means that instead of producing allantoin as the end product of purine oxidation, the pathway ends with uric acid. This leads to humans and many primates having much higher and more highly variable levels of urate in the blood than most other mammals.[3]

Convergent evolution

Urate oxidase is a notable example of the existence of non-homologous isofunctional enzymes, proteins with independent evolutionary origin catalyzing the same chemical reaction.

Besides the cofactorless urate oxidase (UOX), which is found in all three domains of life, other bacterial proteins are known that catalyze the same reaction without being evolutionarily related to UOX. These are two different oxidases (named HpxO and HpyO) that use FAD and NAD+ as cofactors, and one integral membrane protein (named PuuD) that additionally contains a cytochrome c protein domain.[4]

Localization

Urate oxidase is mainly localised in the liver, where it forms a large electron-dense paracrystalline core in many peroxisomes.[5]

Structure

Template:Short description

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The enzyme exists as a tetramer of identical subunits, each containing a possible type 2 copper-binding site.[2]

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.

Function

Template:Infobox enzyme 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.[6]

The active site binds uric acid (and its analogues), allowing it to interact with O2.[7] 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 .[8] 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.[9]

Inhibitors

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.[10]

Clinical significance

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.[11]

It has been proposed that the loss of urate oxidase gene expression has been advantageous to hominoids, 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.[12]

However, uric acid plays a complex physiological role in several processes, including inflammation and danger signalling,[13] and modern purine-rich diets can lead to hyperuricaemia, which is linked to many diseases including an increased risk of developing gout.[3]

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.[14] 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.[15]

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.[16]

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.[17]

Medical uses

Script error: No such module "Unsubst". 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".[18]

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.[19]

See also

References

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