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| ==Crystal Structure of human DAAO in complex with coumpound 12== | | ==Crystal Structure of human DAAO in complex with coumpound 12== |
| <StructureSection load='3w4j' size='340' side='right' caption='[[3w4j]], [[Resolution|resolution]] 2.74Å' scene=''> | | <StructureSection load='3w4j' size='340' side='right'caption='[[3w4j]], [[Resolution|resolution]] 2.74Å' scene=''> |
| == Structural highlights == | | == Structural highlights == |
| <table><tr><td colspan='2'>[[3w4j]] is a 4 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=3W4J OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3W4J FirstGlance]. <br> | | <table><tr><td colspan='2'>[[3w4j]] is a 4 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=3W4J OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3W4J FirstGlance]. <br> |
| </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=2LD:3-HYDROXY-5-(2-PHENYLETHYL)PYRIDIN-2(1H)-ONE'>2LD</scene>, <scene name='pdbligand=FAD:FLAVIN-ADENINE+DINUCLEOTIDE'>FAD</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]] 2.74Å</td></tr> |
| <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3w4i|3w4i]], [[3w4k|3w4k]]</td></tr>
| | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=2LD:3-HYDROXY-5-(2-PHENYLETHYL)PYRIDIN-2(1H)-ONE'>2LD</scene>, <scene name='pdbligand=FAD:FLAVIN-ADENINE+DINUCLEOTIDE'>FAD</scene></td></tr> |
| <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">DAO, DAMOX ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</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=3w4j FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3w4j OCA], [https://pdbe.org/3w4j PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3w4j RCSB], [https://www.ebi.ac.uk/pdbsum/3w4j PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3w4j ProSAT]</span></td></tr> |
| <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/D-amino-acid_oxidase D-amino-acid oxidase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.4.3.3 1.4.3.3] </span></td></tr>
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| <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=3w4j FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3w4j OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3w4j RCSB], [http://www.ebi.ac.uk/pdbsum/3w4j PDBsum]</span></td></tr> | |
| </table> | | </table> |
| == Function == | | == Function == |
| [[http://www.uniprot.org/uniprot/OXDA_HUMAN OXDA_HUMAN]] Regulates the level of the neuromodulator D-serine in the brain. Has high activity towards D-DOPA and contributes to dopamine synthesis. Could act as a detoxifying agent which removes D-amino acids accumulated during aging. Acts on a variety of D-amino acids with a preference for those having small hydrophobic side chains followed by those bearing polar, aromatic, and basic groups. Does not act on acidic amino acids.<ref>PMID:17303072</ref> | | [https://www.uniprot.org/uniprot/OXDA_HUMAN OXDA_HUMAN] Regulates the level of the neuromodulator D-serine in the brain. Has high activity towards D-DOPA and contributes to dopamine synthesis. Could act as a detoxifying agent which removes D-amino acids accumulated during aging. Acts on a variety of D-amino acids with a preference for those having small hydrophobic side chains followed by those bearing polar, aromatic, and basic groups. Does not act on acidic amino acids.<ref>PMID:17303072</ref> |
| <div style="background-color:#fffaf0;">
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| == Publication Abstract from PubMed ==
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| d-Amino acid oxidase (DAAO) catalyzes the oxidation of d-amino acids including d-serine, a coagonist of the N-methyl-d-aspartate receptor. We identified a series of 4-hydroxypyridazin-3(2H)-one derivatives as novel DAAO inhibitors with high potency and substantial cell permeability using fragment-based drug design. Comparisons of complex structures deposited in the Protein Data Bank as well as those determined with in-house fragment hits revealed that a hydrophobic subpocket was formed perpendicular to the flavin ring by flipping Tyr224 in a ligand-dependent manner. We investigated the ability of the initial fragment hit, 3-hydroxy-pyridine-2(1H)-one, to fill this subpocket with the aid of complex structure information. 3-Hydroxy-5-(2-phenylethyl)pyridine-2(1H)-one exhibited the predicted binding mode and demonstrated high inhibitory activity for human DAAO in enzyme- and cell-based assays. We further designed and synthesized 4-hydroxypyridazin-3(2H)-one derivatives, which are equivalent to the 3-hydroxy-pyridine-2(1H)-one series but lack cell toxicity. 6-[2-(3,5-Difluorophenyl)ethyl]-4-hydroxypyridazin-3(2H)-one was found to be effective against MK-801-induced cognitive deficit in the Y-maze.
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| 4-Hydroxypyridazin-3(2H)-one Derivatives as Novel d-Amino Acid Oxidase Inhibitors.,Hondo T, Warizaya M, Niimi T, Namatame I, Yamaguchi T, Nakanishi K, Hamajima T, Harada K, Sakashita H, Matsumoto Y, Orita M, Takeuchi M J Med Chem. 2013 May 9;56(9):3582-92. doi: 10.1021/jm400095b. Epub 2013 Apr 25. PMID:23566269<ref>PMID:23566269</ref>
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| From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
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| </div>
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| ==See Also== | | ==See Also== |
| *[[Amino acid oxidase|Amino acid oxidase]] | | *[[Amino acid oxidase 3D structures|Amino acid oxidase 3D structures]] |
| == References == | | == References == |
| <references/> | | <references/> |
| __TOC__ | | __TOC__ |
| </StructureSection> | | </StructureSection> |
| [[Category: D-amino-acid oxidase]]
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| [[Category: Homo sapiens]] | | [[Category: Homo sapiens]] |
| [[Category: Hamajima, T]] | | [[Category: Large Structures]] |
| [[Category: Harada, K]] | | [[Category: Hamajima T]] |
| [[Category: Hondo, T]] | | [[Category: Harada K]] |
| [[Category: Matsumoto, Y]] | | [[Category: Hondo T]] |
| [[Category: Nakanishi, K]] | | [[Category: Matsumoto Y]] |
| [[Category: Namatame, I]] | | [[Category: Nakanishi K]] |
| [[Category: Niimi, T]] | | [[Category: Namatame I]] |
| [[Category: Orita, M]] | | [[Category: Niimi T]] |
| [[Category: Sakashita, H]] | | [[Category: Orita M]] |
| [[Category: Takeuchi, M]] | | [[Category: Sakashita H]] |
| [[Category: Warizaya, M]] | | [[Category: Takeuchi M]] |
| [[Category: Watanabe, T]] | | [[Category: Warizaya M]] |
| [[Category: Yamaguchi, T]] | | [[Category: Watanabe T]] |
| [[Category: Oxidoreductase-oxidoreductase inhibitor complex]]
| | [[Category: Yamaguchi T]] |