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Kynurenine

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Title: Kynurenine  
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Subject: Indoleamine 2,3-dioxygenase, Tryptophan, DNQX, DCPG, L-AP4
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Kynurenine

Kynurenine
Identifiers
CAS number  N, (D/L)
2922-83-0 (L)
13441-51-5 (D)
PubChem
ChemSpider  YesY
DrugBank
MeSH
ChEBI  YesY
ChEMBL  YesY
Jmol-3D images Image 1
Properties
Molecular formula C10H12N2O3
Molar mass 208.21 g mol−1
Except where noted otherwise, data are given for materials in their standard state (at 25 °C (77 °F), 100 kPa)
 N   YesY/N?)

L-Kynurenine is a metabolite of the amino acid L-tryptophan used in the production of niacin.

Kynurenine is synthesized by the enzyme tryptophan dioxygenase, which is made primarily but not exclusively in the liver, and indoleamine 2,3-dioxygenase, which is made in many tissues in response to immune activation.[1] Kynurenine and its further breakdown products carry out diverse biological functions, including dilating blood vessels during inflammation[2] and regulating the immune response.[3] Some cancers increase kynurenine production, which increases tumor growth.[1]

Evidence suggests that increased kynurenine production may precipitate depressive symptoms associated with interferon treatment for hepatitis C.[4] Cognitive deficits in schizophrenia are associated with imbalances in the enzymes that break down kynurenine.[5] Kynurenine production is increased in Alzheimer's disease[6] and cardiovascular disease[7] where its metabolites are associated with cognitive deficits[8] and depressive symptoms.[9] Kynurenine is also associated with tics.[10][11]

Kynureninase catabolizes the conversion of kynurenine into anthranilic acid[12] while kynurenine-oxoglutarate transaminase catabolizes its conversion into kynurenic acid. Kynurenine 3-hydroxylase converts kynurenine to 3-hydroxykynurenine.[13]

Kynurenin Pathway Dysfunction

Dysfunctional states of destinct steps of the kynurenine pathway (e.g. kynurenine, kynurenic acid, quinolinic acid, anthranilic acid, 3 -Hydroxykynurenine) have been described for a number of disorders, e.g.:[14]

Downregulation of kynurenine-3-monooxygenase (KMO) can be caused by genetic polymorphisms, cytokines, or both.[15][16] KMO deficiency leads to an accumulation of kynurenine and to a shift within the tryptophan metabolic pathway towards kynurenine acid and anthranilic acid.[17] Kynurenine-3-monooxygenase deficiency is associated with disorders of the brain (e.g. schizophrenia, tic disorders) and of the liver.[18][19][20][21][22]

See also

References

  1. ^ a b Opitz, Christiane A.; Litzenburger, Ulrike M.; Sahm, Felix; Ott, Martina; Tritschler, Isabel; Trump, Saskia; Schumacher, Theresa; Jestaedt, Leonie et al. (2011). "An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor". Nature 478 (7368): 197–203.  
  2. ^ Wang, Yutang; Liu, Hanzhong; McKenzie, Gavin; Witting, Paul K; Stasch, Johannes-Peter; Hahn, Michael; Changsirivathanathamrong, Dechaboon; Wu, Ben J et al. (2010). "Kynurenine is an endothelium-derived relaxing factor produced during inflammation". Nature Medicine 16 (3): 279–85.  
  3. ^ Nguyen, N. T.; Kimura, A.; Nakahama, T.; Chinen, I.; Masuda, K.; Nohara, K.; Fujii-Kuriyama, Y.; Kishimoto, T. (2010). "Aryl hydrocarbon receptor negatively regulates dendritic cell immunogenicity via a kynurenine-dependent mechanism". Proceedings of the National Academy of Sciences 107 (46): 19961.  
  4. ^ Capuron, Lucile; Neurauter, Gabriele; Musselman, Dominique L; Lawson, David H; Nemeroff, Charles B; Fuchs, Dietmar; Miller, Andrew H (2003). "Interferon-alpha–induced changes in tryptophan metabolism". Biological Psychiatry 54 (9): 906–14.  
  5. ^ Wonodi, Ikwunga; Stine, OC; Sathyasaikumar, KV; Roberts, RC; Mitchell, BD; Hong, LE; Kajii, Y; Thaker, GK; Schwarcz, R (2011). "Downregulated Kynurenine 3-Monooxygenase Gene Expression and Enzyme Activity in Schizophrenia and Genetic Association with Schizophrenia Endophenotypes". Archives of General Psychiatry 68 (7): 665–74.  
  6. ^ Guillemin, G. J.; Brew, B. J.; Noonan, C. E.; Takikawa, O.; Cullen, K. M. (2005). "Indoleamine 2,3 dioxygenase and quinolinic acid Immunoreactivity in Alzheimer's disease hippocampus". Neuropathology and Applied Neurobiology 31 (4): 395–404.  
  7. ^ Wirleitner, B.; Rudzite, V.; Neurauter, G.; Murr, C.; Kalnins, U.; Erglis, A.; Trusinskis, K.; Fuchs, D. (2003). "Immune activation and degradation of tryptophan in coronary heart disease". European Journal of Clinical Investigation 33 (7): 550–4.  
  8. ^ Pawlak, D; Bien, B; Pawlak, K; Gulaj, E (2010). "Kynurenine and its metabolites in Alzheimer's disease patients". Advances in Medical Sciences 55 (2): 204–11.  
  9. ^ Swardfager, Walter; Herrmann, Nathan; Dowlati, Yekta; Oh, Paul I.; Kiss, Alexander; Walker, Scott E.; Lanctôt, Krista L. (2009). "Indoleamine 2,3-dioxygenase activation and depressive symptoms in patients with coronary artery disease". Psychoneuroendocrinology 34 (10): 1560–6.  
  10. ^ Hoekstra, Pieter J.; Anderson, George M.; Troost, Pieter W.; Kallenberg, Cees G. M.; Minderaa, Ruud B. (2007). "Plasma kynurenine and related measures in tic disorder patients". European Child & Adolescent Psychiatry 16: 71–7.  
  11. ^ McCreary, Andrew C.; Handley, Sheila L. (1995). "Kynurenine potentiates the DOI head shake in mice". Journal of Psychopharmacology 9 (1): 69–70.  
  12. ^ Kynureninase, European Bioinformatics Institute
  13. ^ Saito, Yoshitaka; Hayaishi, Osamu; Rothberg, Simon (1957-12-01). "Studies on Oxygenases". The Journal of Biological Chemistry 229 (2): 921–34.  
  14. ^ Trevor W. Stone: Kynurenines in the CNS: from endogenous obscurity to therapeutic importance. Progress in Neurobiology 64 (2001) 185–218
  15. ^ http://www.klinikum.uni-muenchen.de/Institut-fuer-Laboratoriumsmedizin/de/forschung/neurobiochemie/index.html (Website in German). Retrieved 26 May 2014
  16. ^ Müller N, Myint AM, Schwarz MJ: (2010) Inflammatory Biomarkers and Depression. Neurotox Res. 19: 308-318.
  17. ^ Ikwunga Wonodi, MD; O. Colin Stine, PhD; Korrapati V. Sathyasaikumar etal.: Downregulated Kynurenine 3-Monooxygenase Gene Expression and Enzyme Activity in Schizophrenia and Genetic Association With Schizophrenia Endophenotypes. Arch Gen Psychiatry. 2011;68(7):665-674
  18. ^ Maria Holtze, MSc, Peter Saetre, PhD, Göran Engberg, et al.: Kynurenine 3-monooxygenase polymorphisms: relevance for kynurenic acid synthesis in patients with schizophrenia and healthy controls. J Psychiatry Neurosci. Jan 2012; 37(1): 53–57.
  19. ^ Brian M.Campbell, Erik Charych,Anna W. Lee, Thomas Möller: Kynurenines in CNS disease: regulation byinflammatory cytokines. Frontiers in Neuroscience. Neuroendocrine Science February 2014, Volume 8, Article 12.
  20. ^ Hoekstra PJ, Anderson GM, Troost PW: Plasma kynurenine and related measures in tic disorder patients. Eur Child Adolesc Psychiatry. 2007 Jun;16 Suppl 1:71-7.
  21. ^ Buness A, Roth A, Herrmann A, Schmitz O, Kamp H, et al. (2014) Identification of Metabolites, Clinical Chemistry Markers and Transcripts Associated with Hepatotoxicity. PLoS ONE 9(5): e97249. doi:10.1371/journal.pone.0097249
  22. ^ Hirata Yukiko, Kawachi Takashi, Sugimura Takashi: Fatty liver induced by injection of L-tryptophan. Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism. Volume 144, Issue 2, 2 October 1967, Pages 233–241.
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