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| | ==Structure of human protoporphyrinogen IX oxidase(R59G)== | | ==Structure of human protoporphyrinogen IX oxidase(R59G)== |
| - | <StructureSection load='4ivm' size='340' side='right' caption='[[4ivm]], [[Resolution|resolution]] 2.77Å' scene=''> | + | <StructureSection load='4ivm' size='340' side='right'caption='[[4ivm]], [[Resolution|resolution]] 2.77Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4ivm]] 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=4IVM OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4IVM FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4ivm]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4IVM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4IVM FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ACJ:5-[2-CHLORO-4-(TRIFLUOROMETHYL)PHENOXY]-2-NITROBENZOIC+ACID'>ACJ</scene>, <scene name='pdbligand=FAD:FLAVIN-ADENINE+DINUCLEOTIDE'>FAD</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACJ:5-[2-CHLORO-4-(TRIFLUOROMETHYL)PHENOXY]-2-NITROBENZOIC+ACID'>ACJ</scene>, <scene name='pdbligand=FAD:FLAVIN-ADENINE+DINUCLEOTIDE'>FAD</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3nks|3nks]], [[4ivo|4ivo]]</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=4ivm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ivm OCA], [https://pdbe.org/4ivm PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4ivm RCSB], [https://www.ebi.ac.uk/pdbsum/4ivm PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4ivm ProSAT]</span></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PPOX ([http://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/Protoporphyrinogen_oxidase Protoporphyrinogen oxidase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.3.3.4 1.3.3.4] </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=4ivm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ivm OCA], [http://pdbe.org/4ivm PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4ivm RCSB], [http://www.ebi.ac.uk/pdbsum/4ivm PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4ivm ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/PPOX_HUMAN PPOX_HUMAN]] Porphyria variegata. Defects in PPOX are the cause of variegate porphyria (VP) [MIM:[http://omim.org/entry/176200 176200]]. Porphyrias are inherited defects in the biosynthesis of heme, resulting in the accumulation and increased excretion of porphyrins or porphyrin precursors. They are classified as erythropoietic or hepatic, depending on whether the enzyme deficiency occurs in red blood cells or in the liver. PV is the most common form of porphyria in South Africa. It is characterized by skin hyperpigmentation and hypertrichosis, abdominal pain, tachycardia, hypertension and neuromuscular disturbances. High fecal levels of protoporphyrin and coproporphyrin, increased urine uroporphyrins and iron overload are typical markers of the disease.<ref>PMID:8852667</ref> <ref>PMID:8673113</ref> <ref>PMID:9763307</ref> | + | [https://www.uniprot.org/uniprot/PPOX_HUMAN PPOX_HUMAN] Porphyria variegata. Defects in PPOX are the cause of variegate porphyria (VP) [MIM:[https://omim.org/entry/176200 176200]. Porphyrias are inherited defects in the biosynthesis of heme, resulting in the accumulation and increased excretion of porphyrins or porphyrin precursors. They are classified as erythropoietic or hepatic, depending on whether the enzyme deficiency occurs in red blood cells or in the liver. PV is the most common form of porphyria in South Africa. It is characterized by skin hyperpigmentation and hypertrichosis, abdominal pain, tachycardia, hypertension and neuromuscular disturbances. High fecal levels of protoporphyrin and coproporphyrin, increased urine uroporphyrins and iron overload are typical markers of the disease.<ref>PMID:8852667</ref> <ref>PMID:8673113</ref> <ref>PMID:9763307</ref> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/PPOX_HUMAN PPOX_HUMAN]] Catalyzes the 6-electron oxidation of protoporphyrinogen-IX to form protoporphyrin-IX. | + | [https://www.uniprot.org/uniprot/PPOX_HUMAN PPOX_HUMAN] Catalyzes the 6-electron oxidation of protoporphyrinogen-IX to form protoporphyrin-IX. |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Protoporphyrinogen oxidase]] | + | [[Category: Large Structures]] |
| - | [[Category: Baifan, W]] | + | [[Category: Baifan W]] |
| - | [[Category: Xiaohong, Q]] | + | [[Category: Xiaohong Q]] |
| - | [[Category: Fad binding]]
| + | |
| - | [[Category: Membrane]]
| + | |
| - | [[Category: Oxidase]]
| + | |
| - | [[Category: Oxidoreductase]]
| + | |
| Structural highlights
Disease
PPOX_HUMAN Porphyria variegata. Defects in PPOX are the cause of variegate porphyria (VP) [MIM:176200. Porphyrias are inherited defects in the biosynthesis of heme, resulting in the accumulation and increased excretion of porphyrins or porphyrin precursors. They are classified as erythropoietic or hepatic, depending on whether the enzyme deficiency occurs in red blood cells or in the liver. PV is the most common form of porphyria in South Africa. It is characterized by skin hyperpigmentation and hypertrichosis, abdominal pain, tachycardia, hypertension and neuromuscular disturbances. High fecal levels of protoporphyrin and coproporphyrin, increased urine uroporphyrins and iron overload are typical markers of the disease.[1] [2] [3]
Function
PPOX_HUMAN Catalyzes the 6-electron oxidation of protoporphyrinogen-IX to form protoporphyrin-IX.
Publication Abstract from PubMed
Defects in the human protoporphyrinogen oxidase (hPPO) gene, resulting in ~50% decreased activity of hPPO, is responsible for the dominantly inherited disorder variegate porphyria (VP). To understand the molecular mechanism of VP, we employed the site-directed mutagenesis, biochemical assays, structural biology, and molecular dynamics simulation studies to investigate VP-causing hPPO mutants. We report here the crystal structures of R59Q and R59G mutants in complex with acifluorfen at a resolution of 2.6 and 2.8 A. The r.m.s.d. of the Calpha atoms of the active site structure of R59G and R59Q with respect to the wild-type was 0.20 and 0.15 A, respectively. However, these highly similar static crystal structures of mutants with the wild-type could not quantitatively explain the observed large differences in their enzymatic activity. To understand how the hPPO mutations affect their catalytic activities, we combined molecular dynamics simulation and statistical analysis to quantitatively understand the molecular mechanism of VP-causing mutants. We have found that the probability of the privileged conformations of hPPO can be correlated very well with the k(cat)/K(m) of PPO (correlation coefficient, R(2) > 0.9), and the catalytic activity of 44 clinically reported VP-causing mutants can be accurately predicted. These results indicated that the VP-causing mutation affect the catalytic activity of hPPO by affecting the ability of hPPO to sample the privileged conformations. The current work, together with our previous crystal structure study on the wild-type hPPO, provided the quantitative structural insight into human variegate porphyria disease.
Quantitative structural insight into human variegate porphyria disease.,Wang B, Wen X, Qin X, Wang Z, Tan Y, Shen Y, Xi Z J Biol Chem. 2013 Apr 26;288(17):11731-40. doi: 10.1074/jbc.M113.459768. Epub, 2013 Mar 6. PMID:23467411[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Deybach JC, Puy H, Robreau AM, Lamoril J, Da Silva V, Grandchamp B, Nordmann Y. Mutations in the protoporphyrinogen oxidase gene in patients with variegate porphyria. Hum Mol Genet. 1996 Mar;5(3):407-10. PMID:8852667
- ↑ Meissner PN, Dailey TA, Hift RJ, Ziman M, Corrigall AV, Roberts AG, Meissner DM, Kirsch RE, Dailey HA. A R59W mutation in human protoporphyrinogen oxidase results in decreased enzyme activity and is prevalent in South Africans with variegate porphyria. Nat Genet. 1996 May;13(1):95-7. PMID:8673113 doi:10.1038/ng0596-95
- ↑ Frank J, Poh-Fitzpatrick MB, King LE Jr, Christiano AM. The genetic basis of "Scarsdale Gourmet Diet" variegate porphyria: a missense mutation in the protoporphyrinogen oxidase gene. Arch Dermatol Res. 1998 Aug;290(8):441-5. PMID:9763307
- ↑ Wang B, Wen X, Qin X, Wang Z, Tan Y, Shen Y, Xi Z. Quantitative structural insight into human variegate porphyria disease. J Biol Chem. 2013 Apr 26;288(17):11731-40. doi: 10.1074/jbc.M113.459768. Epub, 2013 Mar 6. PMID:23467411 doi:10.1074/jbc.M113.459768
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