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Structural basis of kynurenine 3-monooxygenase inhibition

DOI: 10.1038/nature12039 DOI Help
PMID: 23575632 PMID Help

Authors: Marta Amaral (University of Manchester) , Colin Levy (School of Chemistry; Manchester Interdisciplinary Biocentre, The University of Manchester) , Derren Heyes (University of Manchester) , Pierre Lafite (University of Manchester) , Tiago F. Outeiro (Instituto de Medicina Molecular) , Flaviano Giorgini (University of Leicester) , David Leys (School of Chemistry; Manchester Interdisciplinary Biocentre, The University of Manchester) , Nigel S. Scrutton (The University of Manchester)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature

State: Published (Approved)
Published: April 2013

Open Access Open Access

Abstract: 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 models1, 2, 3, 4, 5, as well as in a mouse model of Alzheimer’s disease3. 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 disorders6, as well as cancer7, 8 and several peripheral inflammatory conditions9. 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.

Journal Keywords: Blood-Brain; Catalytic; Crystallography; X-Ray; Cyclopropanes; Drug; Enzyme; Humans; Huntington; Kynurenine; Kynurenine; Models; Molecular; Protein; Reproducibility; Saccharomyces; Structure-Activity Relationship

Subject Areas: Biology and Bio-materials

Instruments: I02-Macromolecular Crystallography , I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength) , I04-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography