6FP1

The crystal structure of P.fluorescens Kynurenine 3-monooxygenase (KMO) in complex with competitive inhibitor No. 1

Summary for 6FP1

• Entry DOI: 10.2210/pdb6fp1/pdb
• Descriptor: Kynurenine 3-monooxygenase, FLAVIN-ADENINE DINUCLEOTIDE, CHLORIDE ION, ... (6 entities in total)
• Functional Keywords: inhibitor, oxidoreductase
• Biological source: Pseudomonas fluorescens
• Total number of polymer chains: 2
• Total formula weight: 103928.62

Authors

Levy, C.W.,Leys, D. (deposition date: 2018-02-08, release date: 2019-08-21, Last modification date: 2024-05-01)

Primary citation

Zhang, S.,Sakuma, M.,Deora, G.S.,Levy, C.W.,Klausing, A.,Breda, C.,Read, K.D.,Edlin, C.D.,Ross, B.P.,Wright Muelas, M.,Day, P.J.,O'Hagan, S.,Kell, D.B.,Schwarcz, R.,Leys, D.,Heyes, D.J.,Giorgini, F.,Scrutton, N.S.
A brain-permeable inhibitor of the neurodegenerative disease target kynurenine 3-monooxygenase prevents accumulation of neurotoxic metabolites.
Commun Biol, 2:271-271, 2019

PubMed Abstract: Dysregulation of the kynurenine pathway (KP) leads to imbalances in neuroactive metabolites associated with the pathogenesis of several neurodegenerative disorders, including Huntington's disease (HD). Inhibition of the enzyme kynurenine 3-monooxygenase (KMO) in the KP normalises these metabolic imbalances and ameliorates neurodegeneration and related phenotypes in several neurodegenerative disease models. KMO is thus a promising candidate drug target for these disorders, but known inhibitors are not brain permeable. Here, 19 new KMO inhibitors have been identified. One of these () is neuroprotective in a HD model but is minimally brain penetrant in mice. The prodrug variant () crosses the blood-brain barrier, releases in the brain, thereby lowering levels of 3-hydroxykynurenine, a toxic KP metabolite linked to neurodegeneration. Prodrug will advance development of targeted therapies against multiple neurodegenerative and neuroinflammatory diseases in which KP likely plays a role, including HD, Alzheimer's disease, and Parkinson's disease.

PubMed: 31372510
DOI: 10.1038/s42003-019-0520-5

Experimental method

X-RAY DIFFRACTION (1.97 Å)