Please use this identifier to cite or link to this item: http://hdl.handle.net/2381/32913
Full metadata record
DC FieldValueLanguage
dc.contributor.authorAmaral, Marta-
dc.contributor.authorLevy, Colin-
dc.contributor.authorHeyes, Derren J.-
dc.contributor.authorLafite, Pierre-
dc.contributor.authorOuteiro, Tiago F.-
dc.contributor.authorGiorgini, Flaviano-
dc.contributor.authorLeys, David-
dc.contributor.authorScrutton, Nigel S.-
dc.date.accessioned2015-08-07T15:16:48Z-
dc.date.available2015-08-07T15:16:48Z-
dc.date.issued2013-04-10-
dc.identifier.citationNature, 2013, 496 (7445), pp. 382-385en
dc.identifier.issn0028-0836-
dc.identifier.urihttp://www.nature.com/nature/journal/v496/n7445/full/nature12039.htmlen
dc.identifier.urihttp://hdl.handle.net/2381/32913-
dc.description.abstractInhibition 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.en
dc.language.isoenen
dc.publisherNature Publishing Groupen
dc.relation.urihttp://www.ncbi.nlm.nih.gov/pubmed/23575632-
dc.rightsCopyright © 2013, the authors, published by Nature Publishing Group. Deposited with reference to the publisher’s archiving policy available on the SHERPA/RoMEO website.en
dc.subjectArginineen
dc.subjectBlood-Brain Barrieren
dc.subjectCatalytic Domainen
dc.subjectCrystallography, X-Rayen
dc.subjectCyclopropanesen
dc.subjectDrug Designen
dc.subjectEnzyme Inhibitorsen
dc.subjectHumansen
dc.subjectHuntington Diseaseen
dc.subjectKynurenineen
dc.subjectKynurenine 3-Monooxygenaseen
dc.subjectModels, Molecularen
dc.subjectMolecular Targeted Therapyen
dc.subjectProtein Conformationen
dc.subjectReproducibility of Resultsen
dc.subjectSaccharomyces cerevisiaeen
dc.subjectStructure-Activity Relationshipen
dc.titleStructural basis of kynurenine 3-monooxygenase inhibitionen
dc.typeJournal Articleen
dc.identifier.doi10.1038/nature12039-
dc.identifier.eissn1476-4687-
dc.description.statusPeer-revieweden
dc.description.versionPost-printen
dc.type.subtypeJournal Article-
pubs.organisational-group/Organisationen
pubs.organisational-group/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGYen
pubs.organisational-group/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/School of Biological Sciencesen
pubs.organisational-group/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/School of Biological Sciences/Department of Geneticsen
pubs.organisational-group/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/Themesen
pubs.organisational-group/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/Themes/Genome Scienceen
pubs.organisational-group/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/Themes/Neuroscience & Behaviouren
Appears in Collections:Published Articles, Dept. of Genetics

Files in This Item:
File Description SizeFormat 
Structural basis of kynurenine 3-monooxygenase inhibition..pdfPost-review (final submitted)904.71 kBAdobe PDFView/Open


Items in LRA are protected by copyright, with all rights reserved, unless otherwise indicated.