title: Targeted deletion of kynurenine 3-monooxygenase in mice: a new tool for studying kynurenine pathway metabolism in periphery and brain.
abstract: Kynurenine 3-monooxygenase (KMO), a pivotal enzyme in the kynurenine pathway (KP) of tryptophan degradation, has been suggested to play a major role in physiological and pathological events involving bioactive KP metabolites. To explore this role in greater detail, we generated mice with a targeted genetic disruption of Kmo and present here the first biochemical and neurochemical characterization of these mutant animals. Kmo(-/-) mice lacked KMO activity but showed no obvious abnormalities in the activity of four additional KP enzymes tested. As expected, Kmo(-/-) mice showed substantial reductions in the levels of its enzymatic product, 3-hydroxykynurenine, in liver, brain, and plasma. Compared with wild-type animals, the levels of the downstream metabolite quinolinic acid were also greatly decreased in liver and plasma of the mutant mice but surprisingly were only slightly reduced (by ∼20%) in the brain. The levels of three other KP metabolites: kynurenine, kynurenic acid, and anthranilic acid, were substantially, but differentially, elevated in the liver, brain, and plasma of Kmo(-/-) mice, whereas the liver and brain content of the major end product of the enzymatic cascade, NAD(+), did not differ between Kmo(-/-) and wild-type animals. When assessed by in vivo microdialysis, extracellular kynurenic acid levels were found to be significantly elevated in the brains of Kmo(-/-) mice. Taken together, these results provide further evidence that KMO plays a key regulatory role in the KP and indicate that Kmo(-/-) mice will be useful for studying tissue-specific functions of individual KP metabolites in health and disease.
authors.affiliation: From the Department of Genetics, University of Leicester, Leicester LE1 7RH, United Kingdom.
authors.forename: Flaviano
authors.initials: F
authors.lastname: Giorgini
authors.forename: Shao-Yi
authors.initials: SY
authors.lastname: Huang
authors.forename: Korrapati V
authors.initials: KV
authors.lastname: Sathyasaikumar
authors.forename: Francesca M
authors.initials: FM
authors.lastname: Notarangelo
authors.forename: Marian A R
authors.initials: MA
authors.lastname: Thomas
authors.forename: Margarita
authors.initials: M
authors.lastname: Tararina
authors.forename: Hui-Qiu
authors.initials: HQ
authors.lastname: Wu
authors.forename: Robert
authors.initials: R
authors.lastname: Schwarcz
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Muchowski
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D017353:Gene Deletion; D055786:Gene Knockout Techniques; D007737:Kynurenine / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism*; D050601:Kynurenine 3-Monooxygenase / Q000235:genetics* / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009928:Organ Specificity; D014364:Tryptophan / Q000378:metabolism
chemical_list: D007737:Kynurenine; D014364:Tryptophan; D050601:Kynurenine 3-Monooxygenase
keywords: Kynurenic Acid; Kynurenine; Kynurenine 3-Monooxygenase; Metabolism; Neurodegeneration; Neuroprotection; Schizophrenia; Tryptophan