ArticleNature communications2017
Structural and mechanistic basis of differentiated inhibitors of the acute pancreatitis target kynurenine-3-monooxygenase.
Article in Nature communications, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed.
- The tryptophan-kynurenine pathway in cardiovascular diseases: mechanistic insights and therapeutic opportunities.Frontiers in cardiovascular medicine · 2026Review
- Kynurenine Pathway Dysregulation in Parkinson's Disease: Insights for Disease Modulation and Therapy.International journal of tryptophan research : IJTR · 2025Review
- Neuroactive Kynurenines as Pharmacological Targets: New Experimental Tools and Exciting Therapeutic Opportunities.Pharmacological reviews · 2024Review
- Review
- The Complex World of Kynurenic Acid: Reflections on Biological Issues and Therapeutic Strategy.International journal of molecular sciences · 2024Review
- Review
- Identification of potent inhibitors of kynurenine-3-monooxygenase from natural products:Heliyon · 2024Article
- DFT modeling of water-assisted hydrogen peroxide formation from a C(4a)-(hydro)peroxyflavin.Turkish journal of chemistry · 2024Article
- Structure-Based Design of Bisubstrate Tetracycline Destructase Inhibitors That Block Flavin Redox Cycling.Journal of medicinal chemistry · 2023Article
- The kynurenine pathway presents multi-faceted metabolic vulnerabilities in cancer.Frontiers in oncology · 2023Review
- Ferroptosis in Rat Lung Tissue during Severe Acute Pancreatitis-Associated Acute Lung Injury: Protection of Qingyi Decoction.Oxidative medicine and cellular longevity · 2023Article
- Simplified quality assessment for small-molecule ligands in the Protein Data Bank.Structure (London, England : 1993) · 2022Article
- Small Molecule Regulators Targeting NADCurrent medicinal chemistry · 2022Article
- Pharmacophore-Based Virtual Screening of Novel Competitive Inhibitors of the Neurodegenerative Disease Target Kynurenine-3-Monooxygenase.Molecules (Basel, Switzerland) · 2021Article
- Tryptophan Metabolism via Kynurenine Pathway: Role in Solid Organ Transplantation.International journal of molecular sciences · 2021Review
- Full-length in meso structure and mechanism of rat kynurenine 3-monooxygenase inhibition.Communications biology · 2021Article
- Advantages of brain penetrating inhibitors of kynurenine-3-monooxygenase for treatment of neurodegenerative diseases.Archives of biochemistry and biophysics · 2021Review
- Structural analyses of the Group A flavin-dependent monooxygenase PieE reveal a sliding FAD cofactor conformation bridging OUT and IN conformations.The Journal of biological chemistry · 2020Article
- Kynurenine-3-monooxygenase: A new direction for the treatment in different diseases.Food science & nutrition · 2020Review
- IDO and Kynurenine Metabolites in Peripheral and CNS Disorders.Frontiers in immunology · 2020Review
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Authors and funding
15 authors.
Funding
Abstract
Kynurenine-3-monooxygenase (KMO) is a key FAD-dependent enzyme of tryptophan metabolism. In animal models, KMO inhibition has shown benefit in neurodegenerative diseases such as Huntington's and Alzheimer's. Most recently it has been identified as a target for acute pancreatitis multiple organ dysfunction syndrome (AP-MODS); a devastating inflammatory condition with a mortality rate in excess of 20%. Here we report and dissect the molecular mechanism of action of three classes of KMO inhibitors with differentiated binding modes and kinetics. Two novel inhibitor classes trap the catalytic flavin in a previously unobserved tilting conformation. This correlates with picomolar affinities, increased residence times and an absence of the peroxide production seen with previous substrate site inhibitors. These structural and mechanistic insights culminated in GSK065(C1) and GSK366(C2), molecules suitable for preclinical evaluation. Moreover, revising the repertoire of flavin dynamics in this enzyme class offers exciting new opportunities for inhibitor design.
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