![]() ![]() The KP begins with oxygenation of L-tryptophan, catalyzed by one of two heme-containing dioxygenases, indoleamine 2, 3-dioxygenase (IDO) or tryptophan 2, 3-dioxygenase (TDO), to yield N-formyl-L-kynurenine. This potentially toxic side reaction should be avoided in the design of drugs targeting the kynurenine pathway for treatment of neurodegenerative disorders. Some KMO ligands promote the reaction of NADPH with O 2 without hydroxylation, resulting in uncoupled formation of H 2O 2. Benzisoxazoles with sub-nM binding to KMO have been developed recently. After the determination of the x-ray crystal structure of yeast KMO, inhibitor design has been facilitated. These compounds showed reduction of QUIN and increased KynA in vivo in rats. The first generation of KMO inhibitors was based on structural analogs of the substrate, L-kynurenine. Kynurenine monooxygenase (KMO) is the ideal target for an inhibitor, since inhibition of it would be expected to decrease the toxic metabolites and increase kynurenic acid (KynA), which is neuroprotective. Thus, inhibitors of enzymes in the kynurenine pathway may be valuable to treat these diseases. Quinolinic acid (QUIN) is an excitotoxic agonist at the NMDA receptor, and has been shown to be elevated in neurodegenerative diseases such as Alzheimer's Disease and Huntington's Disease. Several of the metabolites in the kynurenine pathway, however, are potentially toxic, particularly 3-hydroxykynurenine, 3-hydroxyanthranilic acid, and quinolinic acid. The kynurenine pathway is the major route for tryptophan metabolism in mammals. 3Department of Pharmaceutical Sciences, College of Pharmacy, Mercer University, Atlanta, GA, United States.2Department of Biochemistry, University of Georgia, Athens, GA, United States.1Department of Chemistry, University of Georgia, Athens, GA, United States.Phillips 1,2 *, Emma Carine Iradukunda 1, Tamera Hughes 3 and J.
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