Kynurenine-3-monooxygenase

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Kynurenine-3-monooxygenase
Properties of human protein
Mass / length primary structure 486 amino acids
Secondary to quaternary structure multipass membrane protein
Cofactor FAD
Isoforms 3
Identifier
Gene name KMO
External IDs
Enzyme classification
EC, category 1.14.13.9 ,  monooxygenase
Response type Hydroxylation
Substrate Kynurenine + NADPH + O 2
Products 3-hydroxykynurenine + NADP + + H 2 O
Occurrence
Homology family HOG000251788
Parent taxon Bacteria, fungi, animals

Kynurenine 3-monooxygenase (KMO) is an enzyme which the hydroxylation of kynurenine to 3-hydroxykynurenine catalyzed . This reaction is a part of the catabolism of the amino acid tryptophan and the synthesis of NAD and neurologically active substances. KMO is found in animals and some fungi and bacteria . In humans, it is located in large quantities in the liver , placenta and in the immune system , where it is anchored in the membrane of the mitochondria and protrudes into the cytosol .

Medical importance

Kynurenine-3-monooxygenase deficiency

A reduced enzymatic activity of kynurenine-3-monooxygenase (KMO deficiency) can be caused by genetic polymorphisms or in the context of an inflammatory process by cytokines as well as by the enzymes indolamine-2,3-dioxygenase (IDO) and tryptophan-2,3-dioxygenase (TDO). Typically, there is an accumulation of kynurenine and a shift in tryptophan metabolism towards kynurenic acid, anthranilic acid and their other metabolic products. Such changes are described for diseases of the brain (neurological and psychiatric diseases such as schizophrenia and tic disorders ) and the liver. A common constellation in various inflammatory (e.g. rheumatoid arthritis ), neuropsychiatric and malignant diseases is a simultaneously increased kynurenine / tryptophan ratio due to the accumulation of kynurenine before the next metabolic step, the hydroxylation to 3-hydroxykynurenine as a result of catalysis by kynurenine-3-monooxygenase (KMO).

Upregulation

In pneumococcal meningitis , an increase in the activity of the KMO has been described, which leads to an accumulation of the neurotoxic 3-hydroxykynurenine. This contributes to the neurological damage caused by this infectious disease. Mice infected with cerebral malaria lived three times as long when their KMO was inhibited. A role in Huntington's disease is discussed.

pharmacology

KMO is a target for neurodegenerative diseases discussed because its inhibition, the amount of NMDA receptor - antagonists increased kynurenine.

Catalyzed reaction

L-kynurenine+ NADPH + O 2 + NADP + + H 2 O  
  Hydroxykynurenine

L- kynurenine is converted to 3-hydroxy- L- kynurenine by consuming NADPH and oxygen .

Individual evidence

  1. ^ Norbert Müller: The impact of neuroimmune dysregulation on neuroprotection and neurotoxicity in psychiatric disorders - relation to drug treatment. In: Dialogues Clin Neurosci. 11, 2009, pp. 319-332.
  2. ↑ Robert Dantzer, Jason C. O'Connor, Gregory G. Freund et al .: From inflammation to sickness and depression: when the immune system subjugates the brain. In: Nature Publishing Group. Vol 9, January 2008.
  3. ↑ N. Müller, AM Myint, MJ Schwarz: Inflammatory Biomarkers and Depression. In: Neurotox Res. 19, 2010, pp. 308-318.
  4. ↑ Ikwunga Wonodi, O. Colin Stine, Korrapati V. Sathyasaikumar et al .: Downregulated Kynurenine 3-Monooxygenase Gene Expression and Enzyme Activity in Schizophrenia and Genetic Association With Schizophrenia Endophenotypes. In: Arch Gen Psychiatry . 68, 2011, pp. 665-674.
  5. ↑ Maria Holtze, Peter Saetre, Göran Engberg et al: Kynurenine 3-monooxygenase polymorphisms: relevance for kynurenic acid synthesis in patients with schizophrenia and healthy controls. In: J Psychiatry Neurosci. 37, 2012, pp. 53-57.
  6. ^ Brian M. Campbell, Erik Charych, Anna W. Lee, Thomas Möller: Kynurenines in CNS disease: regulation by inflammatory cytokines. In: Frontiers in Neuroscience. Neuroendocrine Science. Vol. 8, 2014, Article 12.
  7. ^ PJ Hoekstra, GM Anderson, PW Troost: Plasma kynurenine and related measures in tic disorder patients. In: Eur Child Adolesc Psychiatry. 16 Suppl 1, 2007, pp. 71-77.
  8. ↑ Serdar M. Dursun, Gillian Farrar, Sheila L. Handley and others: Elevated plasma kynurenine in Tourette syndrome. In: Molecular and Chemical Neuropathology. 21, 1994, pp. 55-60.
  9. ↑ H. Rickards, SM Dursuna, G. Farrar: Increased plasma kynurenine and its relationship to neopterin and tryptophan in Tourette's syndrome. In: Psychological Medicine. 26, 1996, pp. 857-862.
  10. ↑ Erik Kwidzinski: Involvement of indolamine 2,3-dioxygenase (IDO) in immune regulation of the central nervous system. Dissertation . Humboldt University of Berlin, February 13, 2006, urn: nbn: de: kobv: 11-10059777
  11. ↑ A. Buness, A. Roth, A. Herrmann, O. Schmitz, H. Kamp et al .: Identification of Metabolites, Clinical Chemistry Markers and Transcripts Associated with Hepatotoxicity. In: PLoS ONE . 9, 2014, p. E97249. doi: 10.1371 / journal.pone.0097249
  12. ↑ Hirata Yukiko, Kawachi Takashi, Sugimura Takashi: Fatty liver induced by injection of L-tryptophan. In: Biochimica et Biophysica Acta . (BBA) - Lipids and Lipid Metabolism. 144, 1967, pp. 233-241.
  13. ↑ K. Schroecksnadel, S. Kaser, G. Neurauter et al: Increased Degradation of Tryptophan in Blood of Patients with Rheumatoid Arthritis. In: The Journal of Rheumatology . 30, 2003, p. 9.
  14. ↑ M. Maes, R. Verkerk, S. Bonaccorso et al .: Depressive and anxiety symptoms in the early puerperium are related to increased degradation of tryptophan into kynurenine, a phenomenon which is related to immune activation. In: Life Sci . 71, 2002, pp. 1837-1848.
  15. ↑ CL Bellac, RS Coimbra, S. Christen, SL Leib: Pneumococcal meningitis causes accumulation of neurotoxic kynurenine metabolites in brain regions prone to injury . In: Neurobiol. Dis. tape 24 , no. 2 , November 2006, p. 395-402 , doi : 10.1016 / j.nbd.2006.07.014 , PMID 16956766 .
  16. ↑ CJ Clark, GM Mackay, GA Smythe, S. Bustamante, TW Stone, RS Phillips: Prolonged survival of a murine model of cerebral malaria by kynurenine pathway inhibition . In: Infection and Immunity . tape 73 , no. 8 , August 2005, p. 5249-5251 , doi : 10.1128 / IAI.73.8.5249-5251.2005 , PMID 16041050 , PMC 1201246 (free full text).
  17. ↑ F. Giorgini, P. Guidetti, Q. Nguyen, SC Bennett, PJ Muchowski: A genomic screen in yeast implicates kynurenine 3-monooxygenase as a therapeutic target for Huntington disease . In: Nat Genet . tape 37 , no. 5 , May 2005, pp. 526-531 , doi : 10.1038 / ng1542 , PMID 15806102 , PMC 1449881 (free full text).
  18. ↑ UniProt O15229
  19. ↑ M. Hamann, SE Sander, A. Richter: Effects of the kynurenine 3-hydroxylase inhibitor Ro 61-8048 after intrastriatal injections on the severity of dystonia in the dt sz mutant . In: Eur J Pharmacol . tape 586 , no. 1-3 , May 2008, pp. 156-159 , doi : 10.1016 / j.ejphar.2008.02.052 , PMID 18353306 .
  20. ↑ L. Grégoire, A. Rassoulpour, P. Guidetti et al: Prolonged kynurenine 3-hydroxylase inhibition reduces development of levodopa-induced dyskinesias in parkinsonian monkeys . In: Behav. Brain Res. Band 186 , no. 2 , January 2008, p. 161-167 , doi : 10.1016 / j.bbr.2007.08.007 , PMID 17868931 .
  21. ↑ B. Poeggeler, A. Rassoulpour, HQ Wu, P. Guidetti, RC Roberts, R. Schwarcz: Dopamine receptor activation reveals a novel, kynurenate-sensitive component of striatal N-methyl-D-aspartate neurotoxicity . In: Neuroscience . tape 148 , no. 1 , August 2007, p. 188–197 , doi : 10.1016 / j.neuroscience.2007.05.033 , PMID 17629627 , PMC 2034343 (free full text).

Web links

Wikibooks: Biochemistry and Pathobiochemistry: Tryptophan Metabolism  - Learning and Teaching Materials