Uroporphyrinogen III decarboxylase explained

Uroporphyrinogen III decarboxylase (uroporphyrinogen decarboxylase, or UROD) is an enzyme that in humans is encoded by the UROD gene.^[1]

Function

Uroporphyrinogen III decarboxylase is a homodimeric enzyme 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:

\rightleftharpoons coproporphyrinogen III + 4 CO₂

Clinical significance

Mutations and deficiency in this enzyme are known to cause familial porphyria cutanea tarda and hepatoerythropoietic porphyria.^[1] At least 65 disease-causing mutations in this gene have been discovered.^[2]

Mechanism

At low substrate concentrations, the reaction is believed to follow an ordered route, with the sequential removal of CO₂ 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.

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.^[3] A 2008 report demonstrated that the uncatalyzed rate for UroD's reaction is 10⁻¹⁹ s⁻¹, 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 10²⁴ M⁻¹.^[4]

Further reading

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

External links

Notes and References

1. Web site: Entrez Gene: UROD uroporphyrinogen decarboxylase.
2. Šimčíková D, Heneberg P . Refinement of evolutionary medicine predictions based on clinical evidence for the manifestations of Mendelian diseases . Scientific Reports . 9 . 1 . 18577 . December 2019 . 31819097 . 6901466 . 10.1038/s41598-019-54976-4. 2019NatSR...918577S .
3. Silva PJ, Ramos MJ . 2005 . Density-functional study of mechanisms for the cofactor-free decarboxylation performed by uroporphyrinogen III decarboxylase . J Phys Chem B . 109 . 38. 18195–200 . 10.1021/jp051792s . 16853337 .
4. Lewis CA, Wolfenden R . Uroporphyrinogen decarboxylation as a benchmark for the catalytic proficiency of enzymes . Proc. Natl. Acad. Sci. U.S.A. . 105 . 45 . 17328–33 . November 2008 . 18988736 . 10.1073/pnas.0809838105 . 2582308 . 2008PNAS..10517328L . free .