2aex

From Proteopedia

(Difference between revisions)

Revision as of 08:30, 27 January 2021

The 1.58A Crystal Structure of Human Coproporphyrinogen Oxidase Reveals the Structural Basis of Hereditary Coproporphyria

Structural highlights

2aex is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Gene:	CPOX, CPO, CPX (HUMAN)
Activity:	Coproporphyrinogen oxidase, with EC number 1.3.3.3
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[HEM6_HUMAN] Defects in CPOX are the cause of hereditary coproporphyria (HCP) [MIM:121300]. HCP is an acute hepatic porphyria and an autosomal dominant disease characterized by neuropsychiatric disturbances and skin photosensitivity. Biochemically, there is an overexcretion of coproporphyrin III in the urine and in the feces. HCP is clinically characterized by attacks of abdominal pain, neurological disturbances, and psychiatric symptoms. The symptoms are generally manifested with rapid onset, and can be precipitated by drugs, alcohol, caloric deprivation, infection, endocrine factors or stress. A severe variant form is harderoporphyria, which is characterized by earlier onset attacks, massive excretion of harderoporphyrin in the feces, and a marked decrease of coproporphyrinogen IX oxidase activity.^[1] ^[2] ^[3] ^[4] ^[5] ^[6] ^[7] ^[8] ^[9] ^[10]

Function

[HEM6_HUMAN] Key enzyme in heme biosynthesis. Catalyzes the oxidative decarboxylation of propionic acid side chains of rings A and B of 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

Hereditary coproporphyria is an autosomal dominant disorder resulting from the half-normal activity of coproporphyrinogen oxidase (CPO), a mitochondrial enzyme catalyzing the antepenultimate step in heme biosynthesis. The mechanism by which CPO catalyzes oxidative decarboxylation, in an extraordinary metal- and cofactor-independent manner, is poorly understood. Here, we report the crystal structure of human CPO at 1.58-A resolution. The structure reveals a previously uncharacterized tertiary topology comprising an unusually flat seven-stranded beta-sheet sandwiched by alpha-helices. In the biologically active dimer (K(D) = 5 x 10(-7) M), one monomer rotates relative to the second by approximately 40 degrees to create an intersubunit interface in close proximity to two independent enzymatic sites. The unexpected finding of citrate at the active site allows us to assign Ser-244, His-258, Asn-260, Arg-262, Asp-282, and Arg-332 as residues mediating substrate recognition and decarboxylation. We favor a mechanism in which oxygen serves as the immediate electron acceptor, and a substrate radical or a carbanion with substantial radical character participates in catalysis. Although several mutations in the CPO gene have been described, the molecular basis for how these alterations diminish enzyme activity is unknown. We show that deletion of residues (392-418) encoded by exon six disrupts dimerization. Conversely, harderoporphyria-causing K404E mutation precludes a type I beta-turn from retaining the substrate for the second decarboxylation cycle. Together, these findings resolve several questions regarding CPO catalysis and provide insights into hereditary coproporphyria.

Structural basis of hereditary coproporphyria.,Lee DS, Flachsova E, Bodnarova M, Demeler B, Martasek P, Raman CS Proc Natl Acad Sci U S A. 2005 Oct 4;102(40):14232-7. Epub 2005 Sep 21. PMID:16176984^[11]

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

References

↑ Martasek P, Nordmann Y, Grandchamp B. Homozygous hereditary coproporphyria caused by an arginine to tryptophane substitution in coproporphyrinogen oxidase and common intragenic polymorphisms. Hum Mol Genet. 1994 Mar;3(3):477-80. PMID:8012360
↑ Fujita H, Kondo M, Taketani S, Nomura N, Furuyama K, Akagi R, Nagai T, Terajima M, Galbraith RA, Sassa S. Characterization and expression of cDNA encoding coproporphyrinogen oxidase from a patient with hereditary coproporphyria. Hum Mol Genet. 1994 Oct;3(10):1807-10. PMID:7849704
↑ Lamoril J, Martasek P, Deybach JC, Da Silva V, Grandchamp B, Nordmann Y. A molecular defect in coproporphyrinogen oxidase gene causing harderoporphyria, a variant form of hereditary coproporphyria. Hum Mol Genet. 1995 Feb;4(2):275-8. PMID:7757079
↑ Daimon M, Gojyou E, Sugawara M, Yamatani K, Tominaga M, Sasaki H. A novel missense mutation in exon 4 of the human coproporphyrinogen oxidase gene in two patients with hereditary coproporphyria. Hum Genet. 1997 Feb;99(2):199-201. PMID:9048920
↑ Lamoril J, Deybach JC, Puy H, Grandchamp B, Nordmann Y. Three novel mutations in the coproporphyrinogen oxidase gene. Hum Mutat. 1997;9(1):78-80. PMID:8990017 doi:<78::AID-HUMU17>3.0.CO;2-M 10.1002/(SICI)1098-1004(1997)9:1<78::AID-HUMU17>3.0.CO;2-M
↑ Schreiber WE, Zhang X, Senz J, Jamani A. Hereditary coproporphyria: exon screening by heteroduplex analysis detects three novel mutations in the coproporphyrinogen oxidase gene. Hum Mutat. 1997;10(3):196-200. PMID:9298818 doi:<196::AID-HUMU3>3.0.CO;2-H 10.1002/(SICI)1098-1004(1997)10:3<196::AID-HUMU3>3.0.CO;2-H
↑ Rosipal R, Lamoril J, Puy H, Da Silva V, Gouya L, De Rooij FW, Te Velde K, Nordmann Y, Martasek P, Deybach JC. Systematic analysis of coproporphyrinogen oxidase gene defects in hereditary coproporphyria and mutation update. Hum Mutat. 1999;13(1):44-53. PMID:9888388 doi:<44::AID-HUMU5>3.0.CO;2-Q 10.1002/(SICI)1098-1004(1999)13:1<44::AID-HUMU5>3.0.CO;2-Q
↑ Wiman A, Floderus Y, Harper P. Two novel mutations and coexistence of the 991C>T and the 1339C>T mutation on a single allele in the coproporphyrinogen oxidase gene in Swedish patients with hereditary coproporphyria. J Hum Genet. 2002;47(8):407-12. PMID:12181641 doi:10.1007/s100380200059
↑ To-Figueras J, Badenas C, Enriquez MT, Segura S, Alvarez C, Mila M, Lecha M, Herrero C. Biochemical and genetic characterization of four cases of hereditary coproporphyria in Spain. Mol Genet Metab. 2005 Jun;85(2):160-3. Epub 2005 Feb 25. PMID:15896662 doi:10.1016/j.ymgme.2004.12.012
↑ Akagi R, Inoue R, Muranaka S, Tahara T, Taketani S, Anderson KE, Phillips JD, Sassa S. Dual gene defects involving delta-aminolaevulinate dehydratase and coproporphyrinogen oxidase in a porphyria patient. Br J Haematol. 2006 Jan;132(2):237-43. PMID:16398658 doi:10.1111/j.1365-2141.2005.05852.x
↑ Lee DS, Flachsova E, Bodnarova M, Demeler B, Martasek P, Raman CS. Structural basis of hereditary coproporphyria. Proc Natl Acad Sci U S A. 2005 Oct 4;102(40):14232-7. Epub 2005 Sep 21. PMID:16176984

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/2aex"

@@ Line 1: / Line 1: @@
 ==The 1.58A Crystal Structure of Human Coproporphyrinogen Oxidase Reveals the Structural Basis of Hereditary Coproporphyria==
-<StructureSection load='2aex' size='340' side='right' caption='[[2aex]], [[Resolution|resolution]] 1.58&Aring;' scene=''>
+<StructureSection load='2aex' size='340' side='right'caption='[[2aex]], [[Resolution|resolution]] 1.58&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[2aex]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2AEX OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2AEX FirstGlance]. <br>
+<table><tr><td colspan='2'>[[2aex]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2AEX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2AEX FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CIT:CITRIC+ACID'>CIT</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CIT:CITRIC+ACID'>CIT</scene></td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CPOX, CPO, CPX ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CPOX, CPO, CPX ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
-<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Coproporphyrinogen_oxidase Coproporphyrinogen oxidase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.3.3.3 1.3.3.3] </span></td></tr>
+<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Coproporphyrinogen_oxidase Coproporphyrinogen oxidase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.3.3.3 1.3.3.3] </span></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2aex FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2aex OCA], [http://pdbe.org/2aex PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2aex RCSB], [http://www.ebi.ac.uk/pdbsum/2aex PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2aex ProSAT]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2aex FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2aex OCA], [https://pdbe.org/2aex PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2aex RCSB], [https://www.ebi.ac.uk/pdbsum/2aex PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2aex ProSAT]</span></td></tr>
 </table>
 == Disease ==
-[[http://www.uniprot.org/uniprot/HEM6_HUMAN HEM6_HUMAN]] Defects in CPOX are the cause of hereditary coproporphyria (HCP) [MIM:[http://omim.org/entry/121300 121300]]. HCP is an acute hepatic porphyria and an autosomal dominant disease characterized by neuropsychiatric disturbances and skin photosensitivity. Biochemically, there is an overexcretion of coproporphyrin III in the urine and in the feces. HCP is clinically characterized by attacks of abdominal pain, neurological disturbances, and psychiatric symptoms. The symptoms are generally manifested with rapid onset, and can be precipitated by drugs, alcohol, caloric deprivation, infection, endocrine factors or stress. A severe variant form is harderoporphyria, which is characterized by earlier onset attacks, massive excretion of harderoporphyrin in the feces, and a marked decrease of coproporphyrinogen IX oxidase activity.<ref>PMID:8012360</ref> <ref>PMID:7849704</ref> <ref>PMID:7757079</ref> <ref>PMID:9048920</ref> <ref>PMID:8990017</ref> <ref>PMID:9298818</ref> <ref>PMID:9888388</ref> <ref>PMID:12181641</ref> <ref>PMID:15896662</ref> <ref>PMID:16398658</ref>
+[[https://www.uniprot.org/uniprot/HEM6_HUMAN HEM6_HUMAN]] Defects in CPOX are the cause of hereditary coproporphyria (HCP) [MIM:[https://omim.org/entry/121300 121300]]. HCP is an acute hepatic porphyria and an autosomal dominant disease characterized by neuropsychiatric disturbances and skin photosensitivity. Biochemically, there is an overexcretion of coproporphyrin III in the urine and in the feces. HCP is clinically characterized by attacks of abdominal pain, neurological disturbances, and psychiatric symptoms. The symptoms are generally manifested with rapid onset, and can be precipitated by drugs, alcohol, caloric deprivation, infection, endocrine factors or stress. A severe variant form is harderoporphyria, which is characterized by earlier onset attacks, massive excretion of harderoporphyrin in the feces, and a marked decrease of coproporphyrinogen IX oxidase activity.<ref>PMID:8012360</ref> <ref>PMID:7849704</ref> <ref>PMID:7757079</ref> <ref>PMID:9048920</ref> <ref>PMID:8990017</ref> <ref>PMID:9298818</ref> <ref>PMID:9888388</ref> <ref>PMID:12181641</ref> <ref>PMID:15896662</ref> <ref>PMID:16398658</ref>
 == Function ==
-[[http://www.uniprot.org/uniprot/HEM6_HUMAN HEM6_HUMAN]] Key enzyme in heme biosynthesis. Catalyzes the oxidative decarboxylation of propionic acid side chains of rings A and B of coproporphyrinogen III.
+[[https://www.uniprot.org/uniprot/HEM6_HUMAN HEM6_HUMAN]] Key enzyme in heme biosynthesis. Catalyzes the oxidative decarboxylation of propionic acid side chains of rings A and B of coproporphyrinogen III.
 == Evolutionary Conservation ==
 [[Image:Consurf_key_small.gif|200px|right]]
@@ Line 38: / Line 38: @@
 [[Category: Coproporphyrinogen oxidase]]
 [[Category: Human]]
+[[Category: Large Structures]]
 [[Category: Bodnarova, M]]
 [[Category: Demeler, B]]

2aex

From Proteopedia

Revision as of 08:30, 27 January 2021

The 1.58A Crystal Structure of Human Coproporphyrinogen Oxidase Reveals the Structural Basis of Hereditary Coproporphyria

Structural highlights

Disease

Function

Evolutionary Conservation

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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