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| | ==Structure of human dihydroorotate dehydrogenase in complex with ascofuranone (open-form)== | | ==Structure of human dihydroorotate dehydrogenase in complex with ascofuranone (open-form)== |
| - | <StructureSection load='5zfb' size='340' side='right' caption='[[5zfb]], [[Resolution|resolution]] 2.00Å' scene=''> | + | <StructureSection load='5zfb' size='340' side='right'caption='[[5zfb]], [[Resolution|resolution]] 2.00Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5zfb]] 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=5ZFB OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5ZFB FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5zfb]] 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=5ZFB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5ZFB FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=9BX:3-chloro-4,6-dihydroxy-5-[(2Z,6Z,8E)-11-hydroxy-3,7,11-trimethyl-10-oxododeca-2,6,8-trien-1-yl]-2-methylbenzaldehyde'>9BX</scene>, <scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=FMN:FLAVIN+MONONUCLEOTIDE'>FMN</scene>, <scene name='pdbligand=ORO:OROTIC+ACID'>ORO</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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]] 2Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">DHODH ([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=9BX:3-chloro-4,6-dihydroxy-5-[(2Z,6Z,8E)-11-hydroxy-3,7,11-trimethyl-10-oxododeca-2,6,8-trien-1-yl]-2-methylbenzaldehyde'>9BX</scene>, <scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=FMN:FLAVIN+MONONUCLEOTIDE'>FMN</scene>, <scene name='pdbligand=ORO:OROTIC+ACID'>ORO</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Dihydroorotate_dehydrogenase_(quinone) Dihydroorotate dehydrogenase (quinone)], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.3.5.2 1.3.5.2] </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=5zfb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5zfb OCA], [https://pdbe.org/5zfb PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5zfb RCSB], [https://www.ebi.ac.uk/pdbsum/5zfb PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5zfb 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=5zfb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5zfb OCA], [http://pdbe.org/5zfb PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5zfb RCSB], [http://www.ebi.ac.uk/pdbsum/5zfb PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5zfb ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/PYRD_HUMAN PYRD_HUMAN]] Defects in DHODH are the cause of postaxial acrofacial dysostosis (POADS) [MIM:[http://omim.org/entry/263750 263750]]; also known as Miller syndrome. POADS is characterized by severe micrognathia, cleft lip and/or palate, hypoplasia or aplasia of the posterior elements of the limbs, coloboma of the eyelids and supernumerary nipples. POADS is a very rare disorder: only 2 multiplex families, each consisting of 2 affected siblings born to unaffected, nonconsanguineous parents, have been described among a total of around 30 reported cases.<ref>PMID:19915526</ref> | + | [https://www.uniprot.org/uniprot/PYRD_HUMAN PYRD_HUMAN] Defects in DHODH are the cause of postaxial acrofacial dysostosis (POADS) [MIM:[https://omim.org/entry/263750 263750]; also known as Miller syndrome. POADS is characterized by severe micrognathia, cleft lip and/or palate, hypoplasia or aplasia of the posterior elements of the limbs, coloboma of the eyelids and supernumerary nipples. POADS is a very rare disorder: only 2 multiplex families, each consisting of 2 affected siblings born to unaffected, nonconsanguineous parents, have been described among a total of around 30 reported cases.<ref>PMID:19915526</ref> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/PYRD_HUMAN PYRD_HUMAN]] Catalyzes the conversion of dihydroorotate to orotate with quinone as electron acceptor. | + | [https://www.uniprot.org/uniprot/PYRD_HUMAN PYRD_HUMAN] Catalyzes the conversion of dihydroorotate to orotate with quinone as electron acceptor. |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 5zfb" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 5zfb" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Dihydroorotate dehydrogenase 3D structures|Dihydroorotate dehydrogenase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Amalia, E]] | + | [[Category: Large Structures]] |
| - | [[Category: Harada, S]] | + | [[Category: Amalia E]] |
| - | [[Category: Inaoka, K D]] | + | [[Category: Harada S]] |
| - | [[Category: Kido, Y]] | + | [[Category: Inaoka KD]] |
| - | [[Category: Kita, K]] | + | [[Category: Kido Y]] |
| - | [[Category: Miyazaki, Y]] | + | [[Category: Kita K]] |
| - | [[Category: Moore, L A]] | + | [[Category: Miyazaki Y]] |
| - | [[Category: Nakamura, M]] | + | [[Category: Moore LA]] |
| - | [[Category: Saimoto, H]] | + | [[Category: Nakamura M]] |
| - | [[Category: Sakai, C]] | + | [[Category: Saimoto H]] |
| - | [[Category: Shiba, T]] | + | [[Category: Sakai C]] |
| - | [[Category: Dihydroorotate/orotate]]
| + | [[Category: Shiba T]] |
| - | [[Category: Inhibitor complex]]
| + | |
| - | [[Category: Mitochondrial inner membrane]]
| + | |
| - | [[Category: Oxidoreductase]]
| + | |
| - | [[Category: Rossmann fold]]
| + | |
| - | [[Category: Ubiquinone/ubiquinol]]
| + | |
| Structural highlights
5zfb 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.
| | Method: | X-ray diffraction, Resolution 2Å |
| Ligands: | , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Disease
PYRD_HUMAN Defects in DHODH are the cause of postaxial acrofacial dysostosis (POADS) [MIM:263750; also known as Miller syndrome. POADS is characterized by severe micrognathia, cleft lip and/or palate, hypoplasia or aplasia of the posterior elements of the limbs, coloboma of the eyelids and supernumerary nipples. POADS is a very rare disorder: only 2 multiplex families, each consisting of 2 affected siblings born to unaffected, nonconsanguineous parents, have been described among a total of around 30 reported cases.[1]
Function
PYRD_HUMAN Catalyzes the conversion of dihydroorotate to orotate with quinone as electron acceptor.
Publication Abstract from PubMed
Human dihydroorotate dehydrogenase (HsDHODH) is a key enzyme of pyrimidine de novo biosynthesis pathway. It is located on the mitochondrial inner membrane and contributes to the respiratory chain by shuttling electrons to the ubiquinone pool. We have discovered ascofuranone (1), a natural compound produced by Acremonium sclerotigenum, and its derivatives are a potent class of HsDHODH inhibitors. We conducted a structure-activity relationship study and have identified functional groups of 1 that are essential for the inhibition of HsDHODH enzymatic activity. Furthermore, the binding mode of 1 and its derivatives to HsDHODH was demonstrated by co-crystallographic analysis and we show that these inhibitors bind at the ubiquinone binding site. In addition, the cytotoxicities of 1 and its potent derivatives 7, 8, and 9 were studied using human cultured cancer cells. Interestingly, they showed selective and strong cytotoxicity to cancer cells cultured under microenvironment (hypoxia and nutrient-deprived) conditions. The selectivity ratio of 8 under this microenvironment show the most potent inhibition which was over 1000-fold higher compared to that under normal culture condition. Our studies suggest that under microenvironment conditions, cancer cells heavily depend on the pyrimidine de novo biosynthesis pathway. We also provide the first evidence that 1 and its derivatives are potential lead candidates for drug development which target the HsDHODH of cancer cells living under a tumor microenvironment.
Selective Cytotoxicity of Dihydroorotate Dehydrogenase Inhibitors to Human Cancer Cells Under Hypoxia and Nutrient-Deprived Conditions.,Miyazaki Y, Inaoka DK, Shiba T, Saimoto H, Sakura T, Amalia E, Kido Y, Sakai C, Nakamura M, Moore AL, Harada S, Kita K Front Pharmacol. 2018 Sep 4;9:997. doi: 10.3389/fphar.2018.00997. eCollection, 2018. PMID:30233375[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Ng SB, Buckingham KJ, Lee C, Bigham AW, Tabor HK, Dent KM, Huff CD, Shannon PT, Jabs EW, Nickerson DA, Shendure J, Bamshad MJ. Exome sequencing identifies the cause of a mendelian disorder. Nat Genet. 2010 Jan;42(1):30-5. doi: 10.1038/ng.499. Epub 2009 Nov 13. PMID:19915526 doi:10.1038/ng.499
- ↑ Miyazaki Y, Inaoka DK, Shiba T, Saimoto H, Sakura T, Amalia E, Kido Y, Sakai C, Nakamura M, Moore AL, Harada S, Kita K. Selective Cytotoxicity of Dihydroorotate Dehydrogenase Inhibitors to Human Cancer Cells Under Hypoxia and Nutrient-Deprived Conditions. Front Pharmacol. 2018 Sep 4;9:997. doi: 10.3389/fphar.2018.00997. eCollection, 2018. PMID:30233375 doi:http://dx.doi.org/10.3389/fphar.2018.00997
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