Disease relevance of Kmo

• Kynurenine 3-hydroxylase in brain: species activity differences and effect of gerbil cerebral ischemia [1].
• Delayed increases in the activity of kynurenine 3-hydroxylase occur in several brain regions following transient ischemia in gerbils [1].

High impact information on Kmo

• Inhibition of kynurenine 3-hydroxylase suppresses quinolinic acid synthesis and, therefore, shunts all kynurenine metabolism toward kynurenic acid (KYNA) formation [2].
• Kynurenine 3-hydroxylase inhibition in rats: effects on extracellular kynurenic acid concentration and N-methyl-D-aspartate-induced depolarisation in the striatum [2].
• We have examined whether the kynurenine 3-hydroxylase inhibitor Ro 61-8048 increases extracellular (KYNA) sufficiently to control excessive NMDA receptor function [2].
• The synthesis and structure-activity relationship of a series of 4-aryl-2-hydroxy-4-oxobut-2-enoic acids and esters and 2-amino-4-aryl-4-oxobut-2-enoic acids and esters as potent inhibitors of kynurenine-3-hydroxylase are described [3].
• Lesion-induced increases of the activities of kynurenine-3-hydroxylase (3.6-fold), kynureninase (7.6-fold), kynurenine aminotransferase (1.8-fold), and 3-hydroxyanthranilic acid oxygenase (4.2-fold) likely contributed to the enhanced flux through the pathway in the lesioned striatum [4].

Biological context of Kmo

• The tissue distribution of KH activity in the rat suggested that the majority of active enzyme is located in liver and kidney [5].
• A radiometric assay for kynurenine 3-hydroxylase based on the release of 3H2O during hydroxylation of L-[3,5-3H]kynurenine [5].
• In this paper we describe the synthesis, structure-activity relationship (SAR), and biochemical characterization of N-(4-phenylthiazol-2-yl)benzenesulfonamides as inhibitors of kynurenine 3-hydroxylase [6].
• The most potent of these compounds, m-NBA, has an IC50 of 0.9 +/- 0.1 microM as an inhibitor of kynurenine-3-hydroxylase and of 100 +/- 12 microM as an inhibitor of kynureninase [7].
• After intraperitoneal treatment with FCE 28833A, extracellular brain kynurenic acid levels remained significantly elevated for at least 22 h, rendering this compound a far more effective enhancer of kynurenic acid levels than the previously described kynurenine 3-hydroxylase blocker m-nitrobenzoylalanine [8].

Anatomical context of Kmo

• Kynurenine-3-hydroxylase, an enzyme that is part of the degradative pathway for tryptophan, was present in the cerebral cortex of neonatal rats and exhibited a Km for L-kynurenine close to that of the liver enzyme [9].
• The findings indicate that type B MAO and kynurenine 3-hydroxylase which reside in the outer mitochondrial membranes are susceptible to 2-AAF during the early stages of its hepatocarcinogenesis [10].
• In the present electrophysiological study, the firing pattern of dopamine (DA) neurones of rat ventral tegmental area (VTA) was investigated following pharmacologically elevated endogenous levels of KYNA by means of an inhibitor of kynurenine 3-hydroxylase (PNU 156561A) [11].
• RESULTS: We found age-related differences in the liver tryptophan 2,3-dioxygenase, small intestine indole 2,3-dioxygenase, liver and kidney kynurenine 3-monooxygenase activities, which decreased significantly with age [12].
• Kynurenine 3-monooxygenase activity of rat brain mitochondria determined by high performance liquid chromatography with electrochemical detection [13].

Associations of Kmo with chemical compounds

• Modulation of the kynurenine pathway in search for new neuroprotective agents. Synthesis and preliminary evaluation of (m-nitrobenzoyl)alanine, a potent inhibitor of kynurenine-3-hydroxylase [7].
• However, addition of the kynurenine 3-hydroxylase inhibitor resulted in a significant decrement in the formation of 3-hydroxykynurenine and quinolinate in both blood and brain.These data suggest that the ratio between kynurenate and 3-hydroxykynurenine and/or quinolinate in the brain is a critical determinant of neuronal excitability and viability [14].
• The excitation of dopamine neurons by nicotine (1.5-400 microg/kg i.v.) was antagonized and even reversed into an inhibitory response by elevated levels (four-fold) of the endogenous glutamate receptor antagonist kynurenic acid, as induced by a potent inhibitor of kynurenine 3-hydroxylase (PNU 156561A, 40 mg/kg, i.v., 5-9 h) [15].
• The kynurenine 3-hydroxylase assay is based on the conversion of L-kynurenine to 3-hydroxykynurenine in vitro and the quantification of 3-hydroxykynurenine by high-performance liquid chromatography [1].
• In normal rats, single or multiple injections of the kynurenine 3-hydroxylase inhibitor 4,5-dichlorobenzoylalanine (PNU 156561; 50 mg/kg, i.p.), which results in selective increases in brain KYNA levels, failed to protect cortical neurons against a focal malonate injection [16].

Other interactions of Kmo

• These results challenge the notion that kynurenine 3-hydroxylase inhibition may be neuroprotective, primarily through accumulation of KYNA and subsequent attenuation of NMDA receptor function [2].
• However, the more active enzymes appeared to be kynurenine 3-monooxygenase and 3-hydroxyanthranilate 3,4-dioxygenase [17].

Analytical, diagnostic and therapeutic context of Kmo

• In addition, both compounds blocked rat and gerbil kynurenine 3-hydroxylase after oral administration, with ED50's in the 3-5 mumol/kg range in gerbil brain [6].
• Multifunctional microdialysis probes were used in halothane anaesthetised rats to apply NMDA or QUIN directly to the brain, with or without co-perfusion of KYNA, to record the resulting local depolarisations, and to monitor changes in dialysate KYNA after kynurenine-3-hydroxylase inhibition [18].

References