Kynurenine 3-monooxygenase

Kynurenine 3-monooxygenase is a dimer containing asymmetric subunits == Active site ==

While no scientific literature reports a crystal image of a kynurenine 3-monooxygenase complex with -kynurenine, structural studies of the enzyme in yeast co-crystallized with UPF 648 reveal how the FAD cofactor and substrate are bound in the active site. == Mechanism ==

Kynurenine-3-monooxygenase catalyzes the hydroxylation of -kynurenine to 3-hydroxy--kynurenine with concomitant interconversion of NADPH to NADP+. The reaction mechanism is not entirely known, but is believed to follow mechanisms related to the flavin-dependent monooxygenases. After -kynurenine binds, NADPH reduces FAD and leaves as NADP+. Oxygen then binds and creates an -kynurenine-FAD-hydroperoxide intermediate. This intermediate is the electrophilic source for the hydroxylation reaction, yielding a primary ketimine form of the product and the C4a-hydroxy-FAD. Tautomerization yields 3-hydroxy--kynurenine in complex with the enzyme (E Fl HOH-P). Dissociation of 3-hydroxy--kynurenine and H2O leads to the free enzyme (E Flox). == Biological function==

Kynurenine 3-monooxygenase catalyzes the conversion of -kynurenine to 3-hydroxy--kynurenine, an important bioactive metabolite in the kynurenine pathway. The kynurenine pathway is responsible for over 95% of tryptophan oxidative degradation. -Kynurenine is an important branch point of this metabolic pathway, being converted into the neurotoxin 3-hydroxy--kynurenine via kynurenine 3-monooxygenase, the neuroprotectant kynurenic acid through kynurenine amino transferases, or anthranilic acid by kynureninase. Kynurenine 3-monooxygenase regulates the downstream production of quinolinic acid, which can generate reactive free radicals and activates the NMDA subtype of glutamate receptors, producing excitotoxic lesions in the central nervous system of mammals. Quinolinic acid is also the bioprecursor of NAD+. As a result, regulation at the kynurenine 3-monooxygenase enzyme determines the neurotoxic and neuroprotective potential of the kynurenine pathway. ==Disease relevance==

Kynurenine 3-monooxygenase is an attractive drug target for several neurodegenerative and neuroinflammatory diseases, especially Huntington's, Alzheimer's, and Parkinson's disease. Administration of potent enzyme inhibitors has demonstrated promising pharmacological results. and Drosophila models of Huntington's disease. Kynurenine 3-monooxygenase deficiency, which can be caused by genetic polymorphisms, cytokines, or both, leads to an accumulation of kynurenine and to a shift within the tryptophan metabolic pathway towards kynurenic acid and anthranilic acid. Recent research suggests that hyperphysiologic concentrations of kynurenine in kynurenine 3-monooxygenase-deficient patients results in a shift towards kynurenic acid production, believed to be related to cognitive deficits in predictive pursuit and visuospatial working memory. Kynurenine-3-monooxygenase deficiency is associated with disorders of the brain (e.g. schizophrenia, tic disorders) and of the liver. ==References==