Kynurenine

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Kynurenine
Skeletal formula of L-kynurenine
Ball-and-stick model of the L-kynurenine molecule as a zwitterion
Names
IUPAC name
(S)-2-Amino-4-(2-aminophenyl)- 4-oxo-butanoic acid
Other names
(S)-Kynurenine
Identifiers
343-65-7 (D/L) N
2922-83-0 (L) N
13441-51-5 (D) N
ChEBI CHEBI:57959 YesY
ChEMBL ChEMBL498416 YesY
ChemSpider 141580 YesY
DrugBank DB02070 YesY
Jmol-3D images Image
MeSH Kynurenine
PubChem 846
Properties
C10H12N2O3
Molar mass 208.21 g·mol−1
Except where noted otherwise, data is given for materials in their standard state (at 25 °C (77 °F), 100 kPa)
 N verify (what isYesY/N?)
Infobox references

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[edit]

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][10][20][21]

See also[edit]

References[edit]

  1. ^ a b Opitz CA, Litzenburger UM, Sahm F, Ott M, Tritschler I, Trump S et al. (2011). "An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor". Nature 478 (7368): 197–203. doi:10.1038/nature10491. PMID 21976023. 
  2. ^ Wang Y, Liu H, McKenzie G, Witting PK, Stasch JP, Hahn M et al. (2010). "Kynurenine is an endothelium-derived relaxing factor produced during inflammation". Nature Medicine 16 (3): 279–85. doi:10.1038/nm.2092. PMC 3556275. PMID 20190767. 
  3. ^ Nguyen NT, Kimura A, Nakahama T, Chinen I, Masuda K, Nohara K et al. (2010). "Aryl hydrocarbon receptor negatively regulates dendritic cell immunogenicity via a kynurenine-dependent mechanism". Proceedings of the National Academy of Sciences 107 (46): 19961. doi:10.1073/pnas.1014465107. PMID 21041655. 
  4. ^ Capuron L, Neurauter G, Musselman DL, Lawson DH, Nemeroff CB, Fuchs D et al. (2003). "Interferon-alpha–induced changes in tryptophan metabolism". Biological Psychiatry 54 (9): 906–14. doi:10.1016/S0006-3223(03)00173-2. PMID 14573318. 
  5. ^ Wonodi I, Stine OC, Sathyasaikumar KV, Roberts RC, Mitchell BD, Hong LE et al. (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. doi:10.1001/archgenpsychiatry.2011.71. PMC 3855543. PMID 21727251. 
  6. ^ Guillemin GJ, Brew BJ, Noonan CE, Takikawa O, Cullen KM (2005). "Indoleamine 2,3 dioxygenase and quinolinic acid Immunoreactivity in Alzheimer's disease hippocampus". Neuropathology and Applied Neurobiology 31 (4): 395–404. doi:10.1111/j.1365-2990.2005.00655.x. PMID 16008823. 
  7. ^ Wirleitner B, Rudzite V, Neurauter G, Murr C, Kalnins U, Erglis A et al. (2003). "Immune activation and degradation of tryptophan in coronary heart disease". European Journal of Clinical Investigation 33 (7): 550–4. doi:10.1046/j.1365-2362.2003.01186.x. PMID 12814390. 
  8. ^ Gulaj E, Pawlak K, Bien B, Pawlak D (2010). "Kynurenine and its metabolites in Alzheimer's disease patients". Advances in Medical Sciences 55 (2): 204–11. doi:10.2478/v10039-010-0023-6. PMID 20639188. 
  9. ^ Swardfager W, Herrmann N, Dowlati Y, Oh PI, Kiss A, Walker SE et al. (2009). "Indoleamine 2,3-dioxygenase activation and depressive symptoms in patients with coronary artery disease". Psychoneuroendocrinology 34 (10): 1560–6. doi:10.1016/j.psyneuen.2009.05.019. PMID 19540675. 
  10. ^ a b Hoekstra PJ, Anderson GM, Troost PW, Kallenberg CG, Minderaa RB (2007). "Plasma kynurenine and related measures in tic disorder patients". European Child & Adolescent Psychiatry 16: 71–7. doi:10.1007/s00787-007-1009-1. PMID 17665285. 
  11. ^ McCreary AC, Handley SL (1995). "Kynurenine potentiates the DOI head shake in mice". Journal of Psychopharmacology 9 (1): 69–70. doi:10.1177/026988119500900112. PMID 22298697. 
  12. ^ Kynureninase, European Bioinformatics Institute
  13. ^ Saito Y, Hayaishi O, Rothberg S (1957-12-01). "Studies on Oxygenases". The Journal of Biological Chemistry 229 (2): 921–34. PMID 13502353. 
  14. ^ Trevor W. Stone: Kynurenines in the CNS: from endogenous obscurity to therapeutic importance. Progress in Neurobiology 64 (2001) 185–218
  15. ^ "Neurobiochemie" (in German). 
  16. ^ Müller N, Myint AM, Schwarz MJ (2011). "Inflammatory biomarkers and depression". Neurotox Res 19 (2): 308–18. doi:10.1007/s12640-010-9210-2. PMID 20658274. 
  17. ^ Wonodi I, Stine OC, Sathyasaikumar KV, Roberts RC, Mitchell BD, Hong LE et al. (2011). "Downregulated kynurenine 3-monooxygenase gene expression and enzyme activity in schizophrenia and genetic association with schizophrenia endophenotypes". Arch. Gen. Psychiatry 68 (7): 665–74. doi:10.1001/archgenpsychiatry.2011.71. PMC 3855543. PMID 21727251. 
  18. ^ Holtze M, Saetre P, Engberg G, Schwieler L, Werge T, Andreassen OA et al. (2012). "Kynurenine 3-monooxygenase polymorphisms: relevance for kynurenic acid synthesis in patients with schizophrenia and healthy controls". J Psychiatry Neurosci 37 (1): 53–7. doi:10.1503/jpn.100175. PMC 3244499. PMID 21693093. 
  19. ^ Campbell BM, Charych E, Lee AW, Möller T (2014). "Kynurenines in CNS disease: regulation by inflammatory cytokines". Front Neurosci 8: 12. doi:10.3389/fnins.2014.00012. PMC 3915289. PMID 24567701. 
  20. ^ Buness A, Roth A, Herrmann A, Schmitz O, Kamp H, Busch K 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. PMC 4023975. PMID 24836604. 
  21. ^ Hirata Y, Kawachi T, Sugimura T (1967). "Fatty liver induced by injection of L-tryptophan". Biochim. Biophys. Acta 144 (2): 233–41. doi:10.1016/0005-2760(67)90153-1. PMID 4168935.