Substrate and inhibitor specificity of kynurenine monooxygenase from Cytophaga hutchinsonii

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 k(cat) and k(cat)/Km comparable to or higher than kynurenine. However, kynurenines substituted in the 3-position are competitive inhibitors, with K-I values lower than the Km for kynurenine. Bromination also enhances inhibition, and 3,5-dibromokynurenine is a potent competitive inhibitor with a K-1 value of 1.5 mu M. A pharmacophore model of KMO was developed, and predicted that 3,4-dichlorohippuric acid would be an inhibitor. The K1 for this compound was found to be 34 mu M, thus validating the pharmacophore model. We are using these results and our model to design more potent inhibitors of KMO. (C) 2017 Elsevier Ltd. All rights reserved.