title: Substrate and inhibitor specificity of kynurenine monooxygenase from Cytophaga hutchinsonii.
abstract: Kynurenine monooxygenase (KMO) is a potential drug target for treatment of neurodegenerative disorders such as Huntington's and Alzheimer's diseases. We have evaluated substituted kynurenines as substrates or inhibitors of KMO from Cytophaga hutchinsonii. Kynurenines substituted with a halogen at the 5-position are excellent substrates, with values of kcatand kcat/Kmcomparable to or higher than kynurenine. However, kynurenines substituted in the 3-position are competitive inhibitors, with KIvalues lower than the Kmfor kynurenine. Bromination also enhances inhibition, and 3,5-dibromokynurenine is a potent competitive inhibitor with a KIvalue of 1.5μM. A pharmacophore model of KMO was developed, and predicted that 3,4-dichlorohippuric acid would be an inhibitor. The KIfor this compound was found to be 34μM, thus validating the pharmacophore model. We are using these results and our model to design more potent inhibitors of KMO.
authors.affiliation: Department of Chemistry, University of Georgia, Athens 30602, Georgia; Department of Biochemistry and Molecular Biology, University of Georgia, Athens 30602, Georgia. Electronic address: plp@uga.edu.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Phillips
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Georgia, Athens 30602, Georgia.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Anderson
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Georgia, Athens 30602, Georgia.
authors.forename: Harvey G
authors.initials: HG
authors.lastname: Gentry
authors.affiliation: Center for Drug Design, Department of Pharmaceutical Sciences, College of Pharmacy, Mercer University, Atlanta, GA 30341, USA.
authors.forename: Osman F
authors.initials: OF
authors.lastname: Güner
authors.affiliation: Center for Drug Design, Department of Pharmaceutical Sciences, College of Pharmacy, Mercer University, Atlanta, GA 30341, USA.
authors.forename: J Phillip
authors.initials: JP
authors.lastname: Bowen
mesh_terms: D003589:Cytophaga / Q000201:enzymology*; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D054879:Halogenation; D006801:Humans; D007700:Kinetics; D007737:Kynurenine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D050601:Kynurenine 3-Monooxygenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008958:Models, Molecular; D019636:Neurodegenerative Diseases / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism; D013379:Substrate Specificity
chemical_list: D004791:Enzyme Inhibitors; D007737:Kynurenine; D050601:Kynurenine 3-Monooxygenase
keywords: Drug target; Kynurenine analogue; Neurodegenerative diseases; Pharmacophore model