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

Abstract

The kynurenine pathway is the major route for tryptophan metabolism in mammals. Several of the metabolites in the kynurenine pathway, however, are potentially toxic, particularly 3-hydroxykynurenine, 3-hydroxyanthranilic acid, and quinolinic acid. 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. Thus, inhibitors of enzymes in the kynurenine pathway may be valuable to treat these diseases. 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. The first generation of KMO inhibitors was based on structural analogs of the substrate, L-kynurenine. These compounds showed reduction of QUIN and increased KynA in vivo in rats. After the determination of the x-ray crystal structure of yeast KMO, inhibitor design has been facilitated. Benzisoxazoles with sub-nM binding to KMO have been developed recently. Some KMO ligands promote the reaction of NADPH with O2 without hydroxylation, resulting in uncoupled formation of H2O2. This potentially toxic side reaction should be avoided in the design of drugs targeting the kynurenine pathway for treatment of neurodegenerative disorders.

Systematic Review on the Involvement of the Kynurenine Pathway in Stroke: Pre-clinical and Clinical Evidence

“…Evidence from experimental models of stroke, as presented here, neurodegenerative diseases and other neuropsychiatric conditions such as Alzheimer's disease, Huntington's disease and depression, shows that KMO inhibition prevents neuronal loss and the related cognitive and behavioral changes (5, 7). As the available KMO inhibitors do not cross the blood-brain barrier and KMO is highly expressed in peripheral immune cells such as macrophages, it has been proposed that their peripheral action is responsible for these neuroprotective effects (68). In support of this, peripheral inhibition of KMO leads to sustained elevation in the brain levels of kynurenic acid without increasing quinolinic acid levels in the blood or brain (5).…”

IDO and Kynurenine Metabolites in Peripheral and CNS Disorders

“…In the CNS work has been concentrated on inhibitors of KMO to reduce quinolinic acid synthesis and thereby reduce neural activity and excitotoxicity in neurodegenerative disorders as well as in the suppression of peripheral inflammation, especially in the pancreas (223)(224)(225)(226). A different approach is in the development of KAT inhibitors intended to reduce kynurenic acid formation in psychiatric disorders such as schizophrenia (227)(228)(229)(230).…”

Influence of the presence of the heme cofactor on the JK-loop structure in indoleamine 2,3-dioxygenase 1

“…Owing to its degradation into numerous bioactive metabolites, l-tryptophan (l-Trp) is a less abundant but essential amino acid in mammals (Badawy, 2017;Nienhaus & Nienhaus, 2018;King & Thomas, 2007). Although catabolism of l-tryptophan occurs via four possible pathways, the main route for transforming l-Trp is the kynurenine pathway (KP), which allows the transformation of 95% of the l-tryptophan available from food (Phillips et al, 2019). Through the KP, l-Trp is converted into l-kynurenine to produce essential metabolites such as redox cofactors, neuroprotectors and neurotoxins (Kolodziej et al, 2011).…”

“…Through the KP, l-Trp is converted into l-kynurenine to produce essential metabolites such as redox cofactors, neuroprotectors and neurotoxins (Kolodziej et al, 2011). As a result, the KP confers l-Trp with a central role in many diseases, including disruption of the immune response (in cancer and HIV) and neurological disorders (in Alzheimer's disease, Parkinson's disease and Huntington's disease) (Munn & Mellor, 2013;Mellor et al, 2017;Phillips et al, 2019). Therefore, the enzymes of the KP can be considered to be a set of therapeutic targets.…”