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| ==Crystal Structure of kynurenine 3-monooxygenase - truncated at position 394 plus HIS tag cleaved.== | | ==Crystal Structure of kynurenine 3-monooxygenase - truncated at position 394 plus HIS tag cleaved.== |
| <StructureSection load='4j34' size='340' side='right' caption='[[4j34]], [[Resolution|resolution]] 2.03Å' scene=''> | | <StructureSection load='4j34' size='340' side='right'caption='[[4j34]], [[Resolution|resolution]] 2.03Å' scene=''> |
| == Structural highlights == | | == Structural highlights == |
| <table><tr><td colspan='2'>[[4j34]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Baker's_yeast Baker's yeast]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4J34 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4J34 FirstGlance]. <br> | | <table><tr><td colspan='2'>[[4j34]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Saccharomyces_cerevisiae_S288C Saccharomyces cerevisiae S288C]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4J34 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4J34 FirstGlance]. <br> |
| </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><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]] 2.03Å</td></tr> |
| <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4j2w|4j2w]], [[4j31|4j31]], [[4j33|4j33]], [[4j36|4j36]]</td></tr>
| | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><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">BNA4, YBL098W, YBL0828 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=559292 Baker's yeast])</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=4j34 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4j34 OCA], [https://pdbe.org/4j34 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4j34 RCSB], [https://www.ebi.ac.uk/pdbsum/4j34 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4j34 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/Kynurenine_3-monooxygenase Kynurenine 3-monooxygenase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.14.13.9 1.14.13.9] </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=4j34 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4j34 OCA], [http://pdbe.org/4j34 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4j34 RCSB], [http://www.ebi.ac.uk/pdbsum/4j34 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4j34 ProSAT]</span></td></tr> | |
| </table> | | </table> |
| == Function == | | == Function == |
| [[http://www.uniprot.org/uniprot/KMO_YEAST KMO_YEAST]] Catalyzes the hydroxylation of L-kynurenine (L-Kyn) to form 3-hydroxy-L-kynurenine (L-3OHKyn). Required for synthesis of quinolinic acid.<ref>PMID:12062417</ref> <ref>PMID:15806102</ref> | | [https://www.uniprot.org/uniprot/KMO_YEAST KMO_YEAST] Catalyzes the hydroxylation of L-kynurenine (L-Kyn) to form 3-hydroxy-L-kynurenine (L-3OHKyn). Required for synthesis of quinolinic acid.<ref>PMID:12062417</ref> <ref>PMID:15806102</ref> |
| <div style="background-color:#fffaf0;">
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| == Publication Abstract from PubMed ==
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| Inhibition of kynurenine 3-monooxygenase (KMO), an enzyme in the eukaryotic tryptophan catabolic pathway (that is, kynurenine pathway), leads to amelioration of Huntington's-disease-relevant phenotypes in yeast, fruitfly and mouse models, as well as in a mouse model of Alzheimer's disease. KMO is a flavin adenine dinucleotide (FAD)-dependent monooxygenase and is located in the outer mitochondrial membrane where it converts l-kynurenine to 3-hydroxykynurenine. Perturbations in the levels of kynurenine pathway metabolites have been linked to the pathogenesis of a spectrum of brain disorders, as well as cancer and several peripheral inflammatory conditions. Despite the importance of KMO as a target for neurodegenerative disease, the molecular basis of KMO inhibition by available lead compounds has remained unknown. Here we report the first crystal structure of Saccharomyces cerevisiae KMO, in the free form and in complex with the tight-binding inhibitor UPF 648. UPF 648 binds close to the FAD cofactor and perturbs the local active-site structure, preventing productive binding of the substrate l-kynurenine. Functional assays and targeted mutagenesis reveal that the active-site architecture and UPF 648 binding are essentially identical in human KMO, validating the yeast KMO-UPF 648 structure as a template for structure-based drug design. This will inform the search for new KMO inhibitors that are able to cross the blood-brain barrier in targeted therapies against neurodegenerative diseases such as Huntington's, Alzheimer's and Parkinson's diseases.
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| Structural basis of kynurenine 3-monooxygenase inhibition.,Amaral M, Levy C, Heyes DJ, Lafite P, Outeiro TF, Giorgini F, Leys D, Scrutton NS Nature. 2013 Apr 18;496(7445):382-5. doi: 10.1038/nature12039. Epub 2013 Apr 10. PMID:23575632<ref>PMID:23575632</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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| <div class="pdbe-citations 4j34" style="background-color:#fffaf0;"></div>
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| ==See Also== | | ==See Also== |
| *[[Monooxygenase|Monooxygenase]] | | *[[Monooxygenase 3D structures|Monooxygenase 3D structures]] |
| == References == | | == References == |
| <references/> | | <references/> |
| __TOC__ | | __TOC__ |
| </StructureSection> | | </StructureSection> |
| [[Category: Baker's yeast]] | | [[Category: Large Structures]] |
| [[Category: Kynurenine 3-monooxygenase]] | | [[Category: Saccharomyces cerevisiae S288C]] |
| [[Category: Amaral, M]] | | [[Category: Amaral M]] |
| [[Category: Giorgini, F]] | | [[Category: Giorgini F]] |
| [[Category: Heyes, D J]] | | [[Category: Heyes DJ]] |
| [[Category: Lafite, P]] | | [[Category: Lafite P]] |
| [[Category: Levy, C]] | | [[Category: Levy C]] |
| [[Category: Leys, D]] | | [[Category: Leys D]] |
| [[Category: Outeiro, T F]] | | [[Category: Outeiro TF]] |
| [[Category: Scrutton, N S]] | | [[Category: Scrutton NS]] |
| [[Category: Monooxygenase kynurenine his cleaved]]
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| [[Category: Oxidoreductase]]
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