Kynurenine Explained

-Kynurenine is a metabolite of the amino acid -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.

Kynurenine protects the eye by absorbing UV light, especially in the UVA region (315-400 nm).[4] Kynurenine is present in the lens and retina as one of multiple tryptophan derivatives produced in the eye, including 3-hydroxykynurenine, that together provide UV protection and aid in enhancing visual acuity.[5] [6] The use of kynurenine as a UV filter is consistent with its photostability and low photosensitization, owing to its efficient relaxation from the UV-induced excited state.[7] The concentration of this UV filter decreases with age,[8] and this loss of free kynurenine and the concomitant formation of relatively more photosensitizing kynurenine derivatives and kynurenine-protein conjugates may contribute to the formation of cataracts.[9] [10] [11]

Evidence suggests that increased kynurenine production may precipitate depressive symptoms associated with interferon treatment for hepatitis C.[12] Cognitive deficits in schizophrenia are associated with imbalances in the enzymes that break down kynurenine.[13] Blood levels of kynurenine are reduced in people with bipolar disorder.[14] Kynurenine production is increased in Alzheimer's disease[15] and cardiovascular disease[16] where its metabolites are associated with cognitive deficits[17] and depressive symptoms.[18] Kynurenine is also associated with tics.[19] [20]

Kynureninase catabolizes the conversion of kynurenine into anthranilic acid[21] while kynurenine-oxoglutarate transaminase catabolizes its conversion into kynurenic acid. Kynurenine 3-hydroxylase converts kynurenine to 3-hydroxykynurenine.[22]

Kynurenine has also been identified as one of two compounds that makes up the pigment that gives the goldenrod crab spider its yellow color.[23]

thumb|280px|left|The kynurenine pathway, which connects quinolinic acid to tryptophan. The pathway is named for the first intermediate, kynurenine, which is a precursor to kynurenic acid and 3-hydroxykynurenine.[24]

Kynurenine pathway dysfunction

Dysfunctional states of distinct steps of the kynurenine pathway (such as kynurenine, kynurenic acid, quinolinic acid, anthranilic acid, 3-hydroxykynurenine) have been described for a number of disorders, including:[25]

Downregulation of kynurenine-3-monooxygenase (KMO) can be caused by genetic polymorphisms, cytokines, or both.[28] [29] KMO deficiency leads to an accumulation of kynurenine and to a shift within the tryptophan metabolic pathway towards kynurenine acid and anthranilic acid.[30] Kynurenine-3-monooxygenase deficiency is associated with disorders of the brain (e.g. major depressive disorder, bipolar disorder, schizophrenia, tic disorders) [31] and of the liver.[19] [32] [33] [34] [35]

Drug development

It is hypothesized that the kynurenine pathway is partly responsible for the therapeutic effect of lithium on bipolar disorder. If that is the case, it could be a target of drug discovery.[36] [37]

See also

Notes and References

  1. Opitz CA, Litzenburger UM, Sahm F, Ott M, Tritschler I, Trump S, Schumacher T, Jestaedt L, Schrenk D, Weller M, Jugold M, Guillemin GJ, Miller CL, Lutz C, Radlwimmer B, Lehmann I, von Deimling A, Wick W, Platten M . An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor . Nature . 478 . 7368 . 197–203 . 2011 . 21976023 . 10.1038/nature10491 . 2011Natur.478..197O . free.
  2. Wang Y, Liu H, McKenzie G, Witting PK, Stasch JP, Hahn M, Changsirivathanathamrong D, Wu BJ, Ball HJ, Thomas SR, Kapoor V, Celermajer DS, Mellor AL, Keaney JF, Hunt NH, Stocker R . Kynurenine is an endothelium-derived relaxing factor produced during inflammation . Nature Medicine . 16 . 3 . 279–85 . 2010 . 20190767 . 3556275 . 10.1038/nm.2092.
  3. Nguyen NT, Kimura A, Nakahama T, Chinen I, Masuda K, Nohara K, Fujii-Kuriyama Y, Kishimoto T . Aryl hydrocarbon receptor negatively regulates dendritic cell immunogenicity via a kynurenine-dependent mechanism . Proceedings of the National Academy of Sciences . 107 . 46 . 19961–6 . 2010 . 21041655 . 10.1073/pnas.1014465107 . 2993339. 2010PNAS..10719961N. free .
  4. Sherin . Peter S. . Grilj . Jakob . Tsentalovich . Yuri P. . Vauthey . Eric . 2009-04-09 . Ultrafast Excited-State Dynamics of Kynurenine, a UV Filter of the Human Eye . The Journal of Physical Chemistry B . en . 113 . 14 . 4953–4962 . 10.1021/jp900541b . 1520-6106.
  5. Wood . Andrew M. . Truscott . Roger J. W. . 1993-03-01 . UV Filters in Human Lenses: Tryptophan Catabolism . Experimental Eye Research . 56 . 3 . 317–325 . 10.1006/exer.1993.1041 . 0014-4835.
  6. Truscott . Roger J. W. . Wood . Andrew M. . Carver . John A. . Sheil . Margaret M. . Stutchbury . Glen M. . Zhu . Jiulin . Kilby . Greg W. . 1994-07-11 . A new UV-filter compound in human lenses . FEBS Letters . 348 . 2 . 173–176 . 10.1016/0014-5793(94)00601-6 . 0014-5793.
  7. Tuna . Deniz . Došlić . Nađa . Mališ . Momir . Sobolewski . Andrzej L. . Domcke . Wolfgang . 2015-02-12 . Mechanisms of Photostability in Kynurenines: A Joint Electronic-Structure and Dynamics Study . The Journal of Physical Chemistry B . en . 119 . 6 . 2112–2124 . 10.1021/jp501782v . 1520-6106.
  8. Bova . L. M. . Sweeney . M. H. . Jamie . J. F. . Truscott . R. J. . January 2001 . Major changes in human ocular UV protection with age . Investigative Ophthalmology & Visual Science . 42 . 1 . 200–205 . 0146-0404 . 11133868.
  9. Tsentalovich . Yuri P. . Sherin . Peter S. . Kopylova . Lyudmila V. . Cherepanov . Ivan V. . Grilj . Jakob . Vauthey . Eric . 2011-09-29 . Photochemical properties of UV Filter molecules of the human eye . Investigative Ophthalmology & Visual Science . 52 . 10 . 7687–7696 . 10.1167/iovs.11-8120 . 1552-5783 . 21873681.
  10. Vazquez . Santiago . Aquilina . J. Andrew . Sheil . Margaret M. . Truscott . Roger J. W. . Jamie . Joanne F. . 2002-02-15 . Novel Protein Modification by Kynurenine in Human Lenses* . Journal of Biological Chemistry . 277 . 7 . 4867–4873 . 10.1074/jbc.M107529200 . 0021-9258. free .
  11. Sherin . Peter S. . Grilj . Jakob . Kopylova . Lyudmila V. . Yanshole . Vadim V. . Tsentalovich . Yuri P. . Vauthey . Eric . 2010-09-16 . Photophysics and Photochemistry of the UV Filter Kynurenine Covalently Attached to Amino Acids and to a Model Protein . The Journal of Physical Chemistry B . en . 114 . 36 . 11909–11919 . 10.1021/jp104485k . 1520-6106.
  12. Capuron L, Neurauter G, Musselman DL, Lawson DH, Nemeroff CB, Fuchs D, Miller AH . Interferon-alpha–induced changes in tryptophan metabolism . Biological Psychiatry . 54 . 9 . 906–14 . 2003 . 14573318 . 10.1016/S0006-3223(03)00173-2 . 24079984.
  13. Wonodi I, Stine OC, Sathyasaikumar KV, Roberts RC, Mitchell BD, Hong LE, Kajii Y, Thaker GK, Schwarcz R . 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 . 2011 . 21727251 . 3855543 . 10.1001/archgenpsychiatry.2011.71.
  14. Bartoli . F . Misiak . B . Callovini . T . Cavaleri . D . Cioni . RM . Crocamo . C . Savitz . JB . Carrà . G . The kynurenine pathway in bipolar disorder: a meta-analysis on the peripheral blood levels of tryptophan and related metabolites. . Molecular Psychiatry . 19 October 2020 . 26 . 7 . 3419–3429 . 10.1038/s41380-020-00913-1 . 33077852. 224314102 .
  15. Guillemin GJ, Brew BJ, Noonan CE, Takikawa O, Cullen KM . Indoleamine 2,3 dioxygenase and quinolinic acid Immunoreactivity in Alzheimer's disease hippocampus . Neuropathology and Applied Neurobiology . 31 . 4 . 395–404 . 2005 . 16008823 . 10.1111/j.1365-2990.2005.00655.x . 7754894.
  16. Wirleitner B, Rudzite V, Neurauter G, Murr C, Kalnins U, Erglis A, Trusinskis K, Fuchs D . Immune activation and degradation of tryptophan in coronary heart disease . European Journal of Clinical Investigation . 33 . 7 . 550–4 . 2003 . 12814390 . 10.1046/j.1365-2362.2003.01186.x . 10300941.
  17. Gulaj E, Pawlak K, Bien B, Pawlak D . Kynurenine and its metabolites in Alzheimer's disease patients . Advances in Medical Sciences . 55 . 2 . 204–11 . 2010 . 20639188 . 10.2478/v10039-010-0023-6.
  18. Swardfager W, Herrmann N, Dowlati Y, Oh PI, Kiss A, Walker SE, Lanctôt KL . Indoleamine 2,3-dioxygenase activation and depressive symptoms in patients with coronary artery disease . Psychoneuroendocrinology . 34 . 10 . 1560–6 . 2009 . 19540675 . 10.1016/j.psyneuen.2009.05.019 . 36687413.
  19. Hoekstra PJ, Anderson GM, Troost PW, Kallenberg CG, Minderaa RB . Plasma kynurenine and related measures in tic disorder patients . European Child & Adolescent Psychiatry . 16 . 71–7 . 2007 . 17665285 . 10.1007/s00787-007-1009-1 . 39150343.
  20. McCreary AC, Handley SL . Kynurenine potentiates the DOI head shake in mice . Journal of Psychopharmacology . 9 . 1 . 69–70 . 1995 . 22298697 . 10.1177/026988119500900112 . 28700510.
  21. http://www.ebi.ac.uk/interpro/IEntry?ac=IPR010111 Kynureninase
  22. Saito Y, Hayaishi O, Rothberg S . Studies on Oxygenases . The Journal of Biological Chemistry . 229 . 2 . 921–34 . 1957-12-01 . 10.1016/S0021-9258(19)63696-3 . 13502353 . free .
  23. Oxford. G. S.. Gillespie. R. G.. Evolution and Ecology of Spider Coloration. January 1998. Annual Review of Entomology. 43. 1. 619–643. 10.1146/annurev.ento.43.1.619. 15012400. 6963733 . 0066-4170.
  24. Schwarcz. Robert . John P. Bruno . Paul J. Muchowski . Hui-Qiu Wu. Kynurenines in the Mammalian Brain: When Physiology Meets Pathology. Nature Reviews Neuroscience. July 2012. 13. 465–477. 10.1038/nrn3257. 7. 22678511 . 3681811.
  25. Stone TW . 2001 . Kynurenines in the CNS: from endogenous obscurity to therapeutic importance . Progress in Neurobiology . 64 . 2. 185–218 . 10.1016/s0301-0082(00)00032-0. 11240212 . 6446144.
  26. Liu. Duan. Ray. Balmiki. Neavin. Drew R.. Zhang. Jiabin. Athreya. Arjun P.. Biernacka. Joanna M.. Bobo. William V.. Hall-Flavin. Daniel K.. Skime. Michelle K.. Zhu. Hongjie. Jenkins. Gregory D.. January 10, 2018. Beta-defensin 1, aryl hydrocarbon receptor and plasma kynurenine in major depressive disorder: metabolomics-informed genomics. Translational Psychiatry. 8. 1. 10. 10.1038/s41398-017-0056-8. 2158-3188. 5802574. 29317604.
  27. Kashi . Alex A. . Davis . Ronald W. . Phair . Robert D. . The IDO Metabolic Trap Hypothesis for the Etiology of ME/CFS . Diagnostics . 2019 . 9 . 3 . 82 . 10.3390/diagnostics9030082. 31357483 . 6787624 . free.
  28. Web site: Neurobiochemie . de.
  29. Müller N, Myint AM, Schwarz MJ . Inflammatory biomarkers and depression . Neurotox Res . 19 . 2 . 308–18 . 2011 . 20658274 . 10.1007/s12640-010-9210-2 . 3225744.
  30. Wonodi I, Stine OC, Sathyasaikumar KV, Roberts RC, Mitchell BD, Hong LE, Kajii Y, Thaker GK, Schwarcz R . Downregulated kynurenine 3-monooxygenase gene expression and enzyme activity in schizophrenia and genetic association with schizophrenia endophenotypes . Arch. Gen. Psychiatry . 68 . 7 . 665–74 . 2011 . 21727251 . 3855543 . 10.1001/archgenpsychiatry.2011.71.
  31. Marx W, McGuinness AJ, Rocks T, Ruusunen A, Cleminson J, Walker AJ, Gomes-da-Costa S, Lane M, Sanches M, Diaz AP, Tseng PT, Lin PY, Berk M, Clarke G, O'Neil A, Jacka F, Stubbs B, Carvalho AF, Quevedo J, Soares JC, Fernandes BS. 2020. The kynurenine pathway in major depressive disorder, bipolar disorder, and schizophrenia: a meta-analysis of 101 studies. Molecular Psychiatry. 26. 8. 4158–4178. 10.1038/s41380-020-00951-9. 33230205. 227132820. doi: 10.1038/s41380-020-00951-9. PMID 33230205.
  32. Holtze M, Saetre P, Engberg G, Schwieler L, Werge T, Andreassen OA, Hall H, Terenius L, Agartz I, Jönsson EG, Schalling M, Erhardt S . Kynurenine 3-monooxygenase polymorphisms: relevance for kynurenic acid synthesis in patients with schizophrenia and healthy controls . J Psychiatry Neurosci . 37 . 1 . 53–7 . 2012 . 21693093 . 3244499 . 10.1503/jpn.100175.
  33. Campbell BM, Charych E, Lee AW, Möller T . Kynurenines in CNS disease: regulation by inflammatory cytokines . Front Neurosci . 8 . 12 . 2014 . 24567701 . 3915289 . 10.3389/fnins.2014.00012. free .
  34. Buness A, Roth A, Herrmann A, Schmitz O, Kamp H, Busch K, Suter L . Identification of metabolites, clinical chemistry markers and transcripts associated with hepatotoxicity . PLOS ONE . 9 . 5 . e97249 . 2014 . 24836604 . 4023975 . 10.1371/journal.pone.0097249 . 2014PLoSO...997249B. free .
  35. Hirata Y, Kawachi T, Sugimura T . Fatty liver induced by injection of L-tryptophan . Biochim. Biophys. Acta . 144 . 2 . 233–41 . 1967 . 4168935 . 10.1016/0005-2760(67)90153-1.
  36. Bartoli . Francesco . Cioni . Riccardo M. . Cavaleri . Daniele . Callovini . Tommaso . Crocamo . Cristina . Misiak . Błażej . Savitz . Jonathan B. . Carrà . Giuseppe . The association of kynurenine pathway metabolites with symptom severity and clinical features of bipolar disorder: An overview . European Psychiatry . January 2022 . 65 . 1 . e82 . 10.1192/j.eurpsy.2022.2340 . en . 0924-9338. free . 10281/397221 . free .
  37. Fornaro . Michele . Kardash . Lubna . Novello . Stefano . Fusco . Andrea . Anastasia . Annalisa . De Berardis . Domenico . Perna . Giampaolo . Carta . Mauro Giovanni . Progress in bipolar disorder drug design toward the development of novel therapeutic targets: a clinician’s perspective . Expert Opinion on Drug Discovery . 4 March 2018 . 13 . 3 . 221–228 . 10.1080/17460441.2018.1428554.

This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Kynurenine".

Except where otherwise indicated, Everything.Explained.Today is © Copyright 2009-2024, A B Cryer, All Rights Reserved. Cookie policy.