Modulation of Enzyme Activity in the Kynurenine Pathway by Kynurenine Monooxygenase Inhibition.

摘要: The kynurenine pathway is the major route for tryptophan metabolism in mammals. Several of metabolites pathway, however, are potentially toxic, particularly 3-hydroxykynurenine, 3-hydroxyanthranilic acid, and quinolinic acid. Quinolinic acid (QUIN) an excitotoxic agonist at NMDA receptor, has been shown to be elevated neurodegenerative diseases such as Alzheimer's Disease Huntington's Disease. Thus, inhibitors enzymes may valuable treat these diseases. Kynurenine monooxygenase (KMO) ideal target inhibitor, since inhibition it would expected decrease toxic increase kynurenic (KynA), which neuroprotective. first generation KMO was based on structural analogs substrate, L-kynurenine. These compounds showed reduction QUIN increased KynA vivo rats. After determination x-ray crystal structure yeast KMO, inhibitor design facilitated. Benzisoxazoles with sub-nM binding have developed recently. Some ligands promote reaction NADPH O2 without hydroxylation, resulting uncoupled formation H2O2. This side should avoided drugs targeting treatment disorders.