View source for Uroporphyrinogen III decarboxylase

{{Short description|Mammalian protein found in Homo sapiens}}
{{Infobox_gene}}
'''Uroporphyrinogen III decarboxylase''' ('''uroporphyrinogen decarboxylase''', or '''UROD''') is an [[enzyme]] ({{EnzExplorer|4.1.1.37}}) that in humans is encoded by the ''UROD''  [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: UROD uroporphyrinogen decarboxylase| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=7389}}</ref>

== Function ==

Uroporphyrinogen III decarboxylase is a homodimeric enzyme ({{PDB|1URO}}) that catalyzes the fifth step in [[heme]] biosynthesis, which corresponds to the elimination of [[carboxyl]] groups from the four [[acetate]] side chains of [[uroporphyrinogen III]] to yield [[coproporphyrinogen III]]:
:[[uroporphyrinogen III]] <math>\rightleftharpoons</math> [[coproporphyrinogen III]] + 4 CO<sub>2</sub>

== Clinical significance ==

Mutations and deficiency in this enzyme are known to cause familial [[porphyria cutanea tarda]] and [[hepatoerythropoietic porphyria]].<ref name="entrez"/> At least 65 disease-causing mutations in this gene have been discovered.<ref name = "Šimčíková_2019 - supplementary table S7">{{cite journal | vauthors = Šimčíková D, Heneberg P | title = Refinement of evolutionary medicine predictions based on clinical evidence for the manifestations of Mendelian diseases | journal = Scientific Reports | volume = 9 | issue = 1 | pages = 18577 | date = December 2019 | pmid = 31819097 | pmc = 6901466 | doi = 10.1038/s41598-019-54976-4| bibcode = 2019NatSR...918577S }}</ref>

== Mechanism ==

At low substrate concentrations, the reaction is believed to follow an ordered route, with the sequential removal of CO<sub>2</sub> from the D, A, B, and C rings, whereas at higher substrate/enzyme levels a random route seems to be operative. The enzyme functions as a dimer in solution, and both the enzymes from human and tobacco have been crystallized and solved at good resolutions.

[[Image:Uroporphyrinogen-decarboxylase.svg|thumb|left|400px|The reaction catalyzed by UroD]]
UroD is regarded as an unusual decarboxylase, since it performs decarboxylations without the intervention of any cofactors, unlike the vast majority of decarboxylases. Its mechanism has recently been proposed to proceed through substrate protonation by an [[arginine]] residue.<ref>{{cite journal | vauthors = Silva PJ, Ramos MJ | year = 2005 | title = Density-functional study of mechanisms for the cofactor-free decarboxylation performed by uroporphyrinogen III decarboxylase | journal = J Phys Chem B | volume = 109 | issue = 38| pages = 18195–200 | doi = 10.1021/jp051792s | pmid = 16853337 }}</ref> A 2008 report demonstrated that the uncatalyzed rate for UroD's reaction is 10<sup>−19</sup> s<sup>−1</sup>, so at pH 10 the rate acceleration of UroD relative to the uncatalyzed rate, i.e. catalytic proficiency, is the largest for any enzyme known, 6 x 10<sup>24</sup> M<sup>−1</sup>.<ref name="pmid18988736">{{cite journal |vauthors=Lewis CA, Wolfenden R | title = Uroporphyrinogen decarboxylation as a benchmark for the catalytic proficiency of enzymes | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 105 | issue = 45 | pages = 17328–33 |date=November 2008 | pmid = 18988736 | doi = 10.1073/pnas.0809838105 | pmc = 2582308  | bibcode = 2008PNAS..10517328L | doi-access = free }}</ref>

[[Image:UroD mechanism.svg|thumb|670x670px|Proposed reaction mechanism of uroporphyrinogen III decarboxylase|center]]

==References==
{{reflist}}

==Further reading==
{{refbegin}}
* {{cite journal  |vauthors=Elder GH, Lee GB, Tovey JA |title=Decreased activity of hepatic uroporphyrinogen decarboxylase in sporadic porphyria cutanea tarda. |journal=N. Engl. J. Med. |volume=299 |issue= 6 |pages= 274–8 |year= 1978 |pmid= 661926 |doi=10.1056/NEJM197808102990603  }}
* {{cite journal   |vauthors=de Verneuil H, Bourgeois F, de Rooij F, etal |title=Characterization of a new mutation (R292G) and a deletion at the human uroporphyrinogen decarboxylase locus in two patients with hepatoerythropoietic porphyria. |journal=Hum. Genet. |volume=89 |issue= 5 |pages= 548–52 |year= 1992 |pmid= 1634232 |doi=  10.1007/bf00219182|url=http://repub.eur.nl/pub/58484 |hdl=1765/58484 |s2cid=31811381 |hdl-access=free }}
* {{cite journal   |vauthors=Romana M, Grandchamp B, Dubart A, etal |title=Identification of a new mutation responsible for hepatoerythropoietic porphyria. |journal=Eur. J. Clin. Invest. |volume=21 |issue= 2 |pages= 225–9 |year= 1991 |pmid= 1905636 |doi=10.1111/j.1365-2362.1991.tb01814.x  |s2cid=22358220 }}
* {{cite journal   |vauthors=Garey JR, Harrison LM, Franklin KF, etal |title=Uroporphyrinogen decarboxylase: a splice site mutation causes the deletion of exon 6 in multiple families with porphyria cutanea tarda. |journal=J. Clin. Invest. |volume=86 |issue= 5 |pages= 1416–22 |year= 1990 |pmid= 2243121 |doi=10.1172/JCI114856  | pmc=296884  }}
* {{cite journal   |vauthors=Garey JR, Hansen JL, Harrison LM, etal |title=A point mutation in the coding region of uroporphyrinogen decarboxylase associated with familial porphyria cutanea tarda. |journal=Blood |volume=73 |issue= 4 |pages= 892–5 |year= 1989 |doi=10.1182/blood.V73.4.892.892 |pmid= 2920211 |doi-access=free }}
* {{cite journal   |vauthors=Roméo PH, Raich N, Dubart A, etal |title=Molecular cloning and nucleotide sequence of a complete human uroporphyrinogen decarboxylase cDNA. |journal=J. Biol. Chem. |volume=261 |issue= 21 |pages= 9825–31 |year= 1986 |doi=10.1016/S0021-9258(18)67589-1 |pmid= 3015909 |doi-access=free }}
* {{cite journal   |vauthors=Dubart A, Mattei MG, Raich N, etal |title=Assignment of human uroporphyrinogen decarboxylase (URO-D) to the p34 band of chromosome 1. |journal=Hum. Genet. |volume=73 |issue= 3 |pages= 277–9 |year= 1986 |pmid= 3460962 |doi=10.1007/BF00401245  |s2cid=34478515 }}
* {{cite journal   |vauthors=Romana M, Dubart A, Beaupain D, etal |title=Structure of the gene for human uroporphyrinogen decarboxylase. |journal=Nucleic Acids Res. |volume=15 |issue= 18 |pages= 7343–56 |year= 1987 |pmid= 3658695 |doi=10.1093/nar/15.18.7343  | pmc=306252  }}
* {{cite journal   |vauthors=de Verneuil H, Grandchamp B, Beaumont C, etal |title=Uroporphyrinogen decarboxylase structural mutant (Gly281----Glu) in a case of porphyria. |journal=Science |volume=234 |issue= 4777 |pages= 732–4 |year= 1986 |pmid= 3775362 |doi=10.1126/science.3775362  |bibcode=1986Sci...234..732D }}
* {{cite journal   |vauthors=Roberts AG, Elder GH, De Salamanca RE, etal |title=A mutation (G281E) of the human uroporphyrinogen decarboxylase gene causes both hepatoerythropoietic porphyria and overt familial porphyria cutanea tarda: biochemical and genetic studies on Spanish patients. |journal=J. Invest. Dermatol. |volume=104 |issue= 4 |pages= 500–2 |year= 1995 |pmid= 7706766 |doi=10.1111/1523-1747.ep12605953  |doi-access=free }}
* {{cite journal  |vauthors=Maruyama K, Sugano S |title=Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides. |journal=Gene |volume=138 |issue= 1–2 |pages= 171–4 |year= 1994 |pmid= 8125298 |doi=10.1016/0378-1119(94)90802-8  }}
* {{cite journal   |vauthors=Meguro K, Fujita H, Ishida N, etal |title=Molecular defects of uroporphyrinogen decarboxylase in a patient with mild hepatoerythropoietic porphyria |journal=J. Invest. Dermatol. |volume=102 |issue= 5 |pages= 681–5 |year= 1994 |pmid= 8176248 |doi=10.1111/1523-1747.ep12374134  }}
* {{cite journal   |vauthors=Moran-Jimenez MJ, Ged C, Romana M, etal |title=Uroporphyrinogen decarboxylase: complete human gene sequence and molecular study of three families with hepatoerythropoietic porphyria |journal=Am. J. Hum. Genet. |volume=58 |issue= 4 |pages= 712–21 |year= 1996 |pmid= 8644733 | pmc=1914669  }}
* {{cite journal  |vauthors=McManus JF, Begley CG, Sassa S, Ratnaike S |title=Five new mutations in the uroporphyrinogen decarboxylase gene identified in families with cutaneous porphyria |journal=Blood |volume=88 |issue= 9 |pages= 3589–600 |year= 1996 |doi=10.1182/blood.V88.9.3589.bloodjournal8893589 |pmid= 8896428 |doi-access=free }}
* {{cite journal   |vauthors=Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, etal |title=Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library |journal=Gene |volume=200 |issue= 1–2 |pages= 149–56 |year= 1997 |pmid= 9373149 |doi=10.1016/S0378-1119(97)00411-3  }}
* {{cite journal  |vauthors=Whitby FG, Phillips JD, Kushner JP, Hill CP |title=Crystal structure of human uroporphyrinogen decarboxylase |journal=EMBO J. |volume=17 |issue= 9 |pages= 2463–71 |year= 1998 |pmid= 9564029 |doi= 10.1093/emboj/17.9.2463  | pmc=1170588 }}
* {{cite journal   |vauthors=Mendez M, Sorkin L, Rossetti MV, etal |title=Familial porphyria cutanea tarda: characterization of seven novel uroporphyrinogen decarboxylase mutations and frequency of common hemochromatosis alleles |journal=Am. J. Hum. Genet. |volume=63 |issue= 5 |pages= 1363–75 |year= 1998 |pmid= 9792863 |doi=10.1086/302119  | pmc=1377546  }}
* {{cite journal   |vauthors=Wang H, Long Q, Marty SD, etal |title=A zebrafish model for hepatoerythropoietic porphyria |journal=Nat. Genet. |volume=20 |issue= 3 |pages= 239–43 |year= 1998 |pmid= 9806541 |doi= 10.1038/3041 |s2cid=28379777 }}
* {{cite journal  |vauthors=McManus JF, Begley CG, Sassa S, Ratnaike S |title=Three new mutations in the uroporphyrinogen decarboxylase gene in familial porphyria cutanea tarda. Mutation in brief no. 237. Online |journal=Hum. Mutat. |volume=13 |issue= 5 |pages= 412–413 |year= 1999 |pmid= 10338097 |doi= 10.1002/(SICI)1098-1004(1999)13:5<412::AID-HUMU13>3.0.CO;2-N |doi-access= free }}
* {{cite journal   |vauthors=Christiansen L, Ged C, Hombrados I, etal |title=Screening for mutations in the uroporphyrinogen decarboxylase gene using denaturing gradient gel electrophoresis. Identification and characterization of six novel mutations associated with familial PCT |journal=Hum. Mutat. |volume=14 |issue= 3 |pages= 222–32 |year= 1999 |pmid= 10477430 |doi= 10.1002/(SICI)1098-1004(1999)14:3<222::AID-HUMU5>3.0.CO;2-V |s2cid=245442 |doi-access=free }}
{{refend}}

== External links ==
* {{PDBe-KB2|P06132|Uroporphyrinogen decarboxylase}}

{{PDB Gallery|geneid=7389}}

{{Clear}}
[[Image:Heme synthesis.png|left|framed|Heme synthesis—note that some reactions occur in the [[cytoplasm]] and some in the [[mitochondrion]] (yellow)]]

{{Porphyrin biosynthesis enzymes}}
{{Carbon-carbon lyases}}
{{Enzymes}}
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[[Category:EC 4.1.1]]