|
|
| (One intermediate revision not shown.) |
| Line 3: |
Line 3: |
| | <StructureSection load='5upp' size='340' side='right'caption='[[5upp]], [[Resolution|resolution]] 1.80Å' scene=''> | | <StructureSection load='5upp' size='340' side='right'caption='[[5upp]], [[Resolution|resolution]] 1.80Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5upp]] is a 2 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=5UPP OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5UPP FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5upp]] is a 2 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=5UPP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5UPP FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EPE:4-(2-HYDROXYETHYL)-1-PIPERAZINE+ETHANESULFONIC+ACID'>EPE</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.8Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">FH ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EPE:4-(2-HYDROXYETHYL)-1-PIPERAZINE+ETHANESULFONIC+ACID'>EPE</scene></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Fumarate_hydratase Fumarate hydratase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=4.2.1.2 4.2.1.2] </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=5upp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5upp OCA], [https://pdbe.org/5upp PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5upp RCSB], [https://www.ebi.ac.uk/pdbsum/5upp PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5upp ProSAT]</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=5upp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5upp OCA], [http://pdbe.org/5upp PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5upp RCSB], [http://www.ebi.ac.uk/pdbsum/5upp PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5upp ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/FUMH_HUMAN FUMH_HUMAN]] Defects in FH are the cause of fumarase deficiency (FHD) [MIM:[http://omim.org/entry/606812 606812]]; also known as fumaricaciduria. FHD is characterized by progressive encephalopathy, developmental delay, hypotonia, cerebral atrophy and lactic and pyruvic acidemia.[:]<ref>PMID:9635293</ref> Defects in FH are the cause of hereditary leiomyomatosis and renal cell cancer (HLRCC) [MIM:[http://omim.org/entry/150800 150800]]. A disorder characterized by predisposition to cutaneous and uterine leiomyomas, and papillary type 2 renal cancer which occurs in about 20% of patients.<ref>PMID:11865300</ref> | + | [https://www.uniprot.org/uniprot/FUMH_HUMAN FUMH_HUMAN] Defects in FH are the cause of fumarase deficiency (FHD) [MIM:[https://omim.org/entry/606812 606812]; also known as fumaricaciduria. FHD is characterized by progressive encephalopathy, developmental delay, hypotonia, cerebral atrophy and lactic and pyruvic acidemia.[:]<ref>PMID:9635293</ref> Defects in FH are the cause of hereditary leiomyomatosis and renal cell cancer (HLRCC) [MIM:[https://omim.org/entry/150800 150800]. A disorder characterized by predisposition to cutaneous and uterine leiomyomas, and papillary type 2 renal cancer which occurs in about 20% of patients.<ref>PMID:11865300</ref> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/FUMH_HUMAN FUMH_HUMAN]] Also acts as a tumor suppressor. | + | [https://www.uniprot.org/uniprot/FUMH_HUMAN FUMH_HUMAN] Also acts as a tumor suppressor. |
| | + | <div style="background-color:#fffaf0;"> |
| | + | == Publication Abstract from PubMed == |
| | + | Fumarate hydratases (FHs, fumarases) catalyze the reversible conversion of fumarate into l-malate. FHs are distributed over all organisms and play important roles in energy production, DNA repair and as tumor suppressors. They are very important targets both in the study of human metabolic disorders and as potential therapeutic targets in neglected tropical diseases and tuberculosis. In this study, human FH (HsFH) was characterized by using enzyme kinetics, differential scanning fluorimetry and X-ray crystallography. For the first time, the contribution of both substrates was analyzed simultaneously in a single kinetics assay allowing to quantify the contribution of the reversible reaction for kinetics. The protein was crystallized in the spacegroup C2221 , with unit-cell parameters a = 125.43, b = 148.01, c = 129.76. The structure was solved by molecular replacement and refined at 1.8 A resolution. In our study, a HEPES molecule was found to interact with HsFH at the C-terminal domain (Domain 3), previously described as involved in allosteric regulation, through a set of interactions that includes Lys 467. HsFH catalytic efficiency is higher when in the presence of HEPES. Mutations at residue 467 have already been implicated in genetic disorders caused by FH deficiency, suggesting that the HEPES-binding site may be important for enzyme kinetics. This study contributes to the understanding of the HsFH structure and how it correlates with mutation, enzymatic deficiency and pathology. |
| | + | |
| | + | Structural, biochemical and biophysical characterization of recombinant human fumarate hydratase.,Ajalla Aleixo MA, Rangel VL, Rustiguel JK, de Padua RAP, Nonato MC FEBS J. 2019 May;286(10):1925-1940. doi: 10.1111/febs.14782. Epub 2019 Mar 7. PMID:30761759<ref>PMID:30761759</ref> |
| | + | |
| | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| | + | </div> |
| | + | <div class="pdbe-citations 5upp" style="background-color:#fffaf0;"></div> |
| | | | |
| | ==See Also== | | ==See Also== |
| Line 20: |
Line 28: |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Fumarate hydratase]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Human]]
| + | |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Ajalla, M A]] | + | [[Category: Ajalla MA]] |
| - | [[Category: Nonato, M C]] | + | [[Category: Nonato MC]] |
| - | [[Category: Padua, R A.Pereira de]] | + | [[Category: Pereira de Padua RA]] |
| - | [[Category: Rangel, V L]] | + | [[Category: Rangel VL]] |
| - | [[Category: Rustiguel, J K]] | + | [[Category: Rustiguel JK]] |
| - | [[Category: Fumarase]]
| + | |
| - | [[Category: Hsfh]]
| + | |
| - | [[Category: Lyase]]
| + | |
| Structural highlights
Disease
FUMH_HUMAN Defects in FH are the cause of fumarase deficiency (FHD) [MIM:606812; also known as fumaricaciduria. FHD is characterized by progressive encephalopathy, developmental delay, hypotonia, cerebral atrophy and lactic and pyruvic acidemia.[:][1] Defects in FH are the cause of hereditary leiomyomatosis and renal cell cancer (HLRCC) [MIM:150800. A disorder characterized by predisposition to cutaneous and uterine leiomyomas, and papillary type 2 renal cancer which occurs in about 20% of patients.[2]
Function
FUMH_HUMAN Also acts as a tumor suppressor.
Publication Abstract from PubMed
Fumarate hydratases (FHs, fumarases) catalyze the reversible conversion of fumarate into l-malate. FHs are distributed over all organisms and play important roles in energy production, DNA repair and as tumor suppressors. They are very important targets both in the study of human metabolic disorders and as potential therapeutic targets in neglected tropical diseases and tuberculosis. In this study, human FH (HsFH) was characterized by using enzyme kinetics, differential scanning fluorimetry and X-ray crystallography. For the first time, the contribution of both substrates was analyzed simultaneously in a single kinetics assay allowing to quantify the contribution of the reversible reaction for kinetics. The protein was crystallized in the spacegroup C2221 , with unit-cell parameters a = 125.43, b = 148.01, c = 129.76. The structure was solved by molecular replacement and refined at 1.8 A resolution. In our study, a HEPES molecule was found to interact with HsFH at the C-terminal domain (Domain 3), previously described as involved in allosteric regulation, through a set of interactions that includes Lys 467. HsFH catalytic efficiency is higher when in the presence of HEPES. Mutations at residue 467 have already been implicated in genetic disorders caused by FH deficiency, suggesting that the HEPES-binding site may be important for enzyme kinetics. This study contributes to the understanding of the HsFH structure and how it correlates with mutation, enzymatic deficiency and pathology.
Structural, biochemical and biophysical characterization of recombinant human fumarate hydratase.,Ajalla Aleixo MA, Rangel VL, Rustiguel JK, de Padua RAP, Nonato MC FEBS J. 2019 May;286(10):1925-1940. doi: 10.1111/febs.14782. Epub 2019 Mar 7. PMID:30761759[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Coughlin EM, Christensen E, Kunz PL, Krishnamoorthy KS, Walker V, Dennis NR, Chalmers RA, Elpeleg ON, Whelan D, Pollitt RJ, Ramesh V, Mandell R, Shih VE. Molecular analysis and prenatal diagnosis of human fumarase deficiency. Mol Genet Metab. 1998 Apr;63(4):254-62. PMID:9635293 doi:S1096-7192(98)92684-1
- ↑ Tomlinson IP, Alam NA, Rowan AJ, Barclay E, Jaeger EE, Kelsell D, Leigh I, Gorman P, Lamlum H, Rahman S, Roylance RR, Olpin S, Bevan S, Barker K, Hearle N, Houlston RS, Kiuru M, Lehtonen R, Karhu A, Vilkki S, Laiho P, Eklund C, Vierimaa O, Aittomaki K, Hietala M, Sistonen P, Paetau A, Salovaara R, Herva R, Launonen V, Aaltonen LA. Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nat Genet. 2002 Apr;30(4):406-10. Epub 2002 Feb 25. PMID:11865300 doi:10.1038/ng849
- ↑ Ajalla Aleixo MA, Rangel VL, Rustiguel JK, de Padua RAP, Nonato MC. Structural, biochemical and biophysical characterization of recombinant human fumarate hydratase. FEBS J. 2019 May;286(10):1925-1940. doi: 10.1111/febs.14782. Epub 2019 Mar 7. PMID:30761759 doi:http://dx.doi.org/10.1111/febs.14782
|
