Alternative titles; symbols
HGNC Approved Gene Symbol: KMO
Cytogenetic location: 1q43 Genomic coordinates (GRCh38) : 1:241,532,378-241,595,642 (from NCBI)
Kynurenine 3-monooxygenase (KMO; EC 1.14.13.9) is an NADPH-dependent flavin monooxygenase that catalyzes the hydroxylation of the L-tryptophan metabolite L-kynurenine to form L-3-hydroxykynurenine (summary by Alberati-Giani et al., 1997).
By screening a human liver cDNA library with a partial Drosophila KMO cDNA, Alberati-Giani et al. (1997) isolated cDNAs encoding human KMO. The predicted 486-amino acid human protein shares 47% sequence identity with Drosophila KMO. When expressed in mammalian cells, recombinant human KMO exhibited kinetic properties similar to those of the native human protein. Northern blot analysis revealed that human KMO is expressed as an approximately 2-kb mRNA in liver and placenta, and at lower levels in kidney.
Expression of a mutant huntingtin (HTT; 613004) fragment in yeast, as in neurons, results in the formation of inclusion bodies and confers cellular toxicity. Giorgini et al. (2005) performed a genomewide loss-of-function screen to identify S. cerevisiae gene deletions that suppress toxicity of the mutant huntingtin fragment. Among the 28 suppressors identified, Bna4, the yeast homolog of KMO, was one of the most potent.
By comparing genomic and cDNA sequences, Halford et al. (2001) determined that the KMO gene contains at least 15 exons spanning approximately 68 kb.
By genomic sequence analysis, Halford et al. (2001) determined that the KMO gene overlaps with the OPN3 gene (606695) on chromosome 1q43 and that the 2 genes are transcribed from opposite strands.
Kynurenine 3-monooxygenase (KMO) functions at a key branching point of the kynurenine pathway of tryptophan degradation in mammals. Metabolites in the kynurenine pathway are thought to play an important role in neurodegenerative disorders, including Alzheimer (AD; 104300) and Huntington (HD; 143100) diseases. In these disorders, glutamate receptor-mediated excitotoxicity and free radical formation have been correlated with decreased levels of kynurenic acid (KYNA). Inhibition of KMO shunts the metabolic pathway towards enhanced production of KYNA, which had been shown to reduce neuronal vulnerability in animal models by inhibiting ionotropic excitatory amino acid receptors, and is neuroprotective in animal models of brain ischemia. Zwilling et al. (2011) synthesized a small-molecule prodrug inhibitor of KMO, termed JM6, and found that oral administration of JM6 to rats increased KYNA levels and reduced extracellular glutamate in the brain. In a transgenic mouse model of Alzheimer disease, JM6 prevented spatial memory deficits, anxiety-related behavior, and synaptic loss. JM6 also extended life span, prevented synaptic loss, and decreased microglial activation in a mouse model of Huntington disease. These findings supported a critical link between tryptophan metabolism in the blood and neurodegeneration.
Alberati-Giani, D., Cesura, A. M., Broger, C., Warren, W. D., Rover, S., Malherbe, P. Cloning and functional expression of human kynurenine 3-monooxygenase. FEBS Lett. 410: 407-412, 1997. [PubMed: 9237672] [Full Text: https://doi.org/10.1016/s0014-5793(97)00627-3]
Giorgini, F., Guidetti, P., Nguyen, Q., Bennett, S. C., Muchowski, P. J. A genomic screen in yeast implicates kynurenine 3-monooxygenase as a therapeutic target for Huntington disease. Nature Genet. 37: 526-536, 2005. [PubMed: 15806102] [Full Text: https://doi.org/10.1038/ng1542]
Halford, S., Freedman, M. S., Bellingham, J., Inglis, S. L., Poopalasundaram, S., Soni, B. G., Foster, R. G., Hunt, D. M. Characterization of a novel human opsin gene with wide tissue expression and identification of embedded and flanking genes on chromosome 1q43. Genomics 72: 203-208, 2001. [PubMed: 11401433] [Full Text: https://doi.org/10.1006/geno.2001.6469]
Zwilling, D., Huang, S.-Y., Sathyasaikumar, K. V., Notarangelo, F. M., Guidetti, P., Wu, H.-Q., Lee, J., Truong, J., Andrews-Zwilling, Y., Hsieh, E. W., Louie, J. Y., Wu, T., and 13 others. Kynurenine 3-monooxygenase inhibition in blood ameliorates neurodegeneration. Cell 145: 863-874, 2011. [PubMed: 21640374] [Full Text: https://doi.org/10.1016/j.cell.2011.05.020]