1uro

From Proteopedia

(Difference between revisions)

Revision as of 21:11, 29 September 2014

UROPORPHYRINOGEN DECARBOXYLASE

Structural highlights

1uro is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Activity:	Uroporphyrinogen decarboxylase, with EC number 4.1.1.37
Resources:	FirstGlance, OCA, RCSB, PDBsum

Disease

[DCUP_HUMAN] Defects in UROD are the cause of familial porphyria cutanea tarda (FPCT) [MIM:176100]; also known as porphyria cutanea tarda type II. FPCT is an autosomal dominant disorder characterized by light-sensitive dermatitis, with onset in later life. It is associated with the excretion of large amounts of uroporphyrin in the urine. Iron overload is often present in association with varying degrees of liver damage. Besides the familial form of PCT, a relatively common idiosyncratic form is known in which only the liver enzyme is reduced. This form is referred to as porphyria cutanea tarda "sporadic" type or type I [MIM:176090]. PCT type I occurs sporadically as an unusual accompaniment of common hepatic disorders such as alcohol-associated liver disease.^[1] ^[2] ^[3] ^[4] ^[5] ^[6] ^[7] ^[8] ^[9] ^[10] Defects in UROD are the cause of hepatoerythropoietic porphyria (HEP) [MIM:176100]. HEP is a rare autosomal recessive disorder. It is the severe form of cutaneous porphyria, and presents in infancy. The level of UROD is very low in erythrocytes and cultured skin fibroblasts, suggesting that HEP is the homozygous state for porphyria cutanea tarda.^[11] ^[12] ^[13] ^[14] ^[15] ^[16] ^[17] ^[18] ^[19] ^[20]

Function

[DCUP_HUMAN] Catalyzes the decarboxylation of four acetate groups of uroporphyrinogen-III to yield coproporphyrinogen-III.

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

Uroporphyrinogen decarboxylase (URO-D) catalyzes the fifth step in the heme biosynthetic pathway, converting uroporphyrinogen to coproporphyrinogen by decarboxylating the four acetate side chains of the substrate. This activity is essential in all organisms, and subnormal activity of URO-D leads to the most common form of porphyria in humans, porphyria cutanea tarda (PCT). We have determined the crystal structure of recombinant human URO-D at 1.60 A resolution. The 40.8 kDa protein is comprised of a single domain containing a (beta/alpha)8-barrel with a deep active site cleft formed by loops at the C-terminal ends of the barrel strands. Many conserved residues cluster at this cleft, including the invariant side chains of Arg37, Arg41 and His339, which probably function in substrate binding, and Asp86, Tyr164 and Ser219, which may function in either binding or catalysis. URO-D is a dimer in solution (Kd = 0.1 microM), and this dimer also appears to be formed in the crystal. Assembly of the dimer juxtaposes the active site clefts of the monomers, suggesting a functionally important interaction between the catalytic centers.

Crystal structure of human uroporphyrinogen decarboxylase.,Whitby FG, Phillips JD, Kushner JP, Hill CP EMBO J. 1998 May 1;17(9):2463-71. PMID:9564029^[21]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Garey JR, Harrison LM, Franklin KF, Metcalf KM, Radisky ES, Kushner JP. Uroporphyrinogen decarboxylase: a splice site mutation causes the deletion of exon 6 in multiple families with porphyria cutanea tarda. J Clin Invest. 1990 Nov;86(5):1416-22. PMID:2243121 doi:http://dx.doi.org/10.1172/JCI114856
↑ Phillips JD, Parker TL, Schubert HL, Whitby FG, Hill CP, Kushner JP. Functional consequences of naturally occurring mutations in human uroporphyrinogen decarboxylase. Blood. 2001 Dec 1;98(12):3179-85. PMID:11719352
↑ Garey JR, Hansen JL, Harrison LM, Kennedy JB, Kushner JP. A point mutation in the coding region of uroporphyrinogen decarboxylase associated with familial porphyria cutanea tarda. Blood. 1989 Mar;73(4):892-5. PMID:2920211
↑ Roberts AG, Elder GH, De Salamanca RE, Herrero C, Lecha M, Mascaro JM. 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. 1995 Apr;104(4):500-2. PMID:7706766
↑ McManus JF, Begley CG, Sassa S, Ratnaike S. Five new mutations in the uroporphyrinogen decarboxylase gene identified in families with cutaneous porphyria. Blood. 1996 Nov 1;88(9):3589-600. PMID:8896428
↑ Mendez M, Sorkin L, Rossetti MV, Astrin KH, del C Batlle AM, Parera VE, Aizencang G, Desnick RJ. Familial porphyria cutanea tarda: characterization of seven novel uroporphyrinogen decarboxylase mutations and frequency of common hemochromatosis alleles. Am J Hum Genet. 1998 Nov;63(5):1363-75. PMID:9792863
↑ 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. 1999;13(5):412. PMID:10338097 doi:<412::AID-HUMU11>3.0.CO;2-T 10.1002/(SICI)1098-1004(1999)13:5<412::AID-HUMU11>3.0.CO;2-T
↑ Christiansen L, Ged C, Hombrados I, Brons-Poulsen J, Fontanellas A, de Verneuil H, Horder M, Petersen NE. 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. 1999;14(3):222-32. PMID:10477430 doi:<222::AID-HUMU5>3.0.CO;2-V 10.1002/(SICI)1098-1004(1999)14:3<222::AID-HUMU5>3.0.CO;2-V
↑ Brady JJ, Jackson HA, Roberts AG, Morgan RR, Whatley SD, Rowlands GL, Darby C, Shudell E, Watson R, Paiker J, Worwood MW, Elder GH. Co-inheritance of mutations in the uroporphyrinogen decarboxylase and hemochromatosis genes accelerates the onset of porphyria cutanea tarda. J Invest Dermatol. 2000 Nov;115(5):868-74. PMID:11069625 doi:jid148
↑ Cappellini MD, Martinez di Montemuros F, Tavazzi D, Fargion S, Pizzuti A, Comino A, Cainelli T, Fiorelli G. Seven novel point mutations in the uroporphyrinogen decarboxylase (UROD) gene in patients with familial porphyria cutanea tarda (f-PCT). Hum Mutat. 2001 Apr;17(4):350. PMID:11295834 doi:10.1002/humu.35
↑ McManus JF, Begley CG, Sassa S, Ratnaike S. Five new mutations in the uroporphyrinogen decarboxylase gene identified in families with cutaneous porphyria. Blood. 1996 Nov 1;88(9):3589-600. PMID:8896428
↑ Moran-Jimenez MJ, Ged C, Romana M, Enriquez De Salamanca R, Taieb A, Topi G, D'Alessandro L, de Verneuil H. Uroporphyrinogen decarboxylase: complete human gene sequence and molecular study of three families with hepatoerythropoietic porphyria. Am J Hum Genet. 1996 Apr;58(4):712-21. PMID:8644733
↑ de Verneuil H, Grandchamp B, Beaumont C, Picat C, Nordmann Y. Uroporphyrinogen decarboxylase structural mutant (Gly281----Glu) in a case of porphyria. Science. 1986 Nov 7;234(4777):732-4. PMID:3775362
↑ Romana M, Grandchamp B, Dubart A, Amselem S, Chabret C, Nordmann Y, Goossens M, Romeo PH. Identification of a new mutation responsible for hepatoerythropoietic porphyria. Eur J Clin Invest. 1991 Apr;21(2):225-9. PMID:1905636
↑ de Verneuil H, Bourgeois F, de Rooij F, Siersema PD, Wilson JH, Grandchamp B, Nordmann Y. Characterization of a new mutation (R292G) and a deletion at the human uroporphyrinogen decarboxylase locus in two patients with hepatoerythropoietic porphyria. Hum Genet. 1992 Jul;89(5):548-52. PMID:1634232
↑ Meguro K, Fujita H, Ishida N, Akagi R, Kurihara T, Galbraith RA, Kappas A, Zabriskie JB, Toback AC, Harber LC, et al.. Molecular defects of uroporphyrinogen decarboxylase in a patient with mild hepatoerythropoietic porphyria. J Invest Dermatol. 1994 May;102(5):681-5. PMID:8176248
↑ Ged C, Ozalla D, Herrero C, Lecha M, Mendez M, de Verneuil H, Mascaro JM. Description of a new mutation in hepatoerythropoietic porphyria and prenatal exclusion of a homozygous fetus. Arch Dermatol. 2002 Jul;138(7):957-60. PMID:12071824
↑ Armstrong DK, Sharpe PC, Chambers CR, Whatley SD, Roberts AG, Elder GH. Hepatoerythropoietic porphyria: a missense mutation in the UROD gene is associated with mild disease and an unusual porphyrin excretion pattern. Br J Dermatol. 2004 Oct;151(4):920-3. PMID:15491440 doi:BJD6101
↑ Phillips JD, Whitby FG, Stadtmueller BM, Edwards CQ, Hill CP, Kushner JP. Two novel uroporphyrinogen decarboxylase (URO-D) mutations causing hepatoerythropoietic porphyria (HEP). Transl Res. 2007 Feb;149(2):85-91. PMID:17240319 doi:10.1016/j.trsl.2006.08.006
↑ To-Figueras J, Phillips JD, Gonzalez-Lopez JM, Badenas C, Madrigal I, Gonzalez-Romaris EM, Ramos C, Aguirre JM, Herrero C. Hepatoerythropoietic porphyria due to a novel mutation in the uroporphyrinogen decarboxylase gene. Br J Dermatol. 2011 Sep;165(3):499-505. doi: 10.1111/j.1365-2133.2011.10453.x., Epub 2011 Aug 18. PMID:21668429 doi:10.1111/j.1365-2133.2011.10453.x
↑ Whitby FG, Phillips JD, Kushner JP, Hill CP. Crystal structure of human uroporphyrinogen decarboxylase. EMBO J. 1998 May 1;17(9):2463-71. PMID:9564029 doi:10.1093/emboj/17.9.2463

1 Structural highlights
2 Disease
3 Function
4 Evolutionary Conservation
5 Publication Abstract from PubMed
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/1uro"

@@ Line 1: / Line 1: @@
-{{STRUCTURE_1uro|  PDB=1uro  |  SCENE=  }}
+==UROPORPHYRINOGEN DECARBOXYLASE==
-===UROPORPHYRINOGEN DECARBOXYLASE===
+<StructureSection load='1uro' size='340' side='right' caption='[[1uro]], [[Resolution|resolution]] 1.80&Aring;' scene=''>
-{{ABSTRACT_PUBMED_9564029}}
+== Structural highlights ==
+<table><tr><td colspan='2'>[[1uro]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1URO OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1URO FirstGlance]. <br>
-==Disease==
+</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=BME:BETA-MERCAPTOETHANOL'>BME</scene><br>
-[[http://www.uniprot.org/uniprot/DCUP_HUMAN DCUP_HUMAN]] Defects in UROD are the cause of familial porphyria cutanea tarda (FPCT) [MIM:[http://omim.org/entry/176100 176100]]; also known as porphyria cutanea tarda type II. FPCT is an autosomal dominant disorder characterized by light-sensitive dermatitis, with onset in later life. It is associated with the excretion of large amounts of uroporphyrin in the urine. Iron overload is often present in association with varying degrees of liver damage. Besides the familial form of PCT, a relatively common idiosyncratic form is known in which only the liver enzyme is reduced. This form is referred to as porphyria cutanea tarda "sporadic" type or type I [MIM:[http://omim.org/entry/176090 176090]]. PCT type I occurs sporadically as an unusual accompaniment of common hepatic disorders such as alcohol-associated liver disease.<ref>PMID:2243121</ref><ref>PMID:11719352</ref><ref>PMID:2920211</ref><ref>PMID:7706766</ref><ref>PMID:8896428</ref><ref>PMID:9792863</ref><ref>PMID:10338097</ref><ref>PMID:10477430</ref><ref>PMID:11069625</ref><ref>PMID:11295834</ref>  Defects in UROD are the cause of hepatoerythropoietic porphyria (HEP) [MIM:[http://omim.org/entry/176100 176100]]. HEP is a rare autosomal recessive disorder. It is the severe form of cutaneous porphyria, and presents in infancy. The level of UROD is very low in erythrocytes and cultured skin fibroblasts, suggesting that HEP is the homozygous state for porphyria cutanea tarda.<ref>PMID:8896428</ref><ref>PMID:8644733</ref><ref>PMID:3775362</ref><ref>PMID:1905636</ref><ref>PMID:1634232</ref><ref>PMID:8176248</ref><ref>PMID:12071824</ref><ref>PMID:15491440</ref><ref>PMID:17240319</ref><ref>PMID:21668429</ref>
+<tr><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Uroporphyrinogen_decarboxylase Uroporphyrinogen decarboxylase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=4.1.1.37 4.1.1.37] </span></td></tr>
+<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1uro FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1uro OCA], [http://www.rcsb.org/pdb/explore.do?structureId=1uro RCSB], [http://www.ebi.ac.uk/pdbsum/1uro PDBsum]</span></td></tr>
-==Function==
+<table>
+== Disease ==
+[[http://www.uniprot.org/uniprot/DCUP_HUMAN DCUP_HUMAN]] Defects in UROD are the cause of familial porphyria cutanea tarda (FPCT) [MIM:[http://omim.org/entry/176100 176100]]; also known as porphyria cutanea tarda type II. FPCT is an autosomal dominant disorder characterized by light-sensitive dermatitis, with onset in later life. It is associated with the excretion of large amounts of uroporphyrin in the urine. Iron overload is often present in association with varying degrees of liver damage. Besides the familial form of PCT, a relatively common idiosyncratic form is known in which only the liver enzyme is reduced. This form is referred to as porphyria cutanea tarda "sporadic" type or type I [MIM:[http://omim.org/entry/176090 176090]]. PCT type I occurs sporadically as an unusual accompaniment of common hepatic disorders such as alcohol-associated liver disease.<ref>PMID:2243121</ref> <ref>PMID:11719352</ref> <ref>PMID:2920211</ref> <ref>PMID:7706766</ref> <ref>PMID:8896428</ref> <ref>PMID:9792863</ref> <ref>PMID:10338097</ref> <ref>PMID:10477430</ref> <ref>PMID:11069625</ref> <ref>PMID:11295834</ref>   Defects in UROD are the cause of hepatoerythropoietic porphyria (HEP) [MIM:[http://omim.org/entry/176100 176100]]. HEP is a rare autosomal recessive disorder. It is the severe form of cutaneous porphyria, and presents in infancy. The level of UROD is very low in erythrocytes and cultured skin fibroblasts, suggesting that HEP is the homozygous state for porphyria cutanea tarda.<ref>PMID:8896428</ref> <ref>PMID:8644733</ref> <ref>PMID:3775362</ref> <ref>PMID:1905636</ref> <ref>PMID:1634232</ref> <ref>PMID:8176248</ref> <ref>PMID:12071824</ref> <ref>PMID:15491440</ref> <ref>PMID:17240319</ref> <ref>PMID:21668429</ref>
+== Function ==
 [[http://www.uniprot.org/uniprot/DCUP_HUMAN DCUP_HUMAN]] Catalyzes the decarboxylation of four acetate groups of uroporphyrinogen-III to yield coproporphyrinogen-III.
+== Evolutionary Conservation ==
+[[Image:Consurf_key_small.gif|200px|right]]
+Check<jmol>
+  <jmolCheckbox>
+    <scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/ur/1uro_consurf.spt"</scriptWhenChecked>
+    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
+    <text>to colour the structure by Evolutionary Conservation</text>
+  </jmolCheckbox>
+</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/chain_selection.php?pdb_ID=2ata ConSurf].
+<div style="clear:both"></div>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Uroporphyrinogen decarboxylase (URO-D) catalyzes the fifth step in the heme biosynthetic pathway, converting uroporphyrinogen to coproporphyrinogen by decarboxylating the four acetate side chains of the substrate. This activity is essential in all organisms, and subnormal activity of URO-D leads to the most common form of porphyria in humans, porphyria cutanea tarda (PCT). We have determined the crystal structure of recombinant human URO-D at 1.60 A resolution. The 40.8 kDa protein is comprised of a single domain containing a (beta/alpha)8-barrel with a deep active site cleft formed by loops at the C-terminal ends of the barrel strands. Many conserved residues cluster at this cleft, including the invariant side chains of Arg37, Arg41 and His339, which probably function in substrate binding, and Asp86, Tyr164 and Ser219, which may function in either binding or catalysis. URO-D is a dimer in solution (Kd = 0.1 microM), and this dimer also appears to be formed in the crystal. Assembly of the dimer juxtaposes the active site clefts of the monomers, suggesting a functionally important interaction between the catalytic centers.
-==About this Structure==
+Crystal structure of human uroporphyrinogen decarboxylase.,Whitby FG, Phillips JD, Kushner JP, Hill CP EMBO J. 1998 May 1;17(9):2463-71. PMID:9564029<ref>PMID:9564029</ref>
-[[1uro]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1URO OCA].
-==Reference==
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-<ref group="xtra">PMID:009564029</ref><references group="xtra"/><references/>
+</div>
+== References ==
+<references/>
+__TOC__
+</StructureSection>
 [[Category: Homo sapiens]]
 [[Category: Uroporphyrinogen decarboxylase]]

1uro

From Proteopedia

Revision as of 21:11, 29 September 2014

UROPORPHYRINOGEN DECARBOXYLASE

Structural highlights

Disease

Function

Evolutionary Conservation

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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