Chemistry:Kynurenine

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l-Kynurenine
Skeletal formula of L-kynurenine
Ball-and-stick model of the L-kynurenine molecule as a zwitterion
Names
Preferred IUPAC name
(2S)-2-Amino-4-(2-aminophenyl)-4-oxo-butanoic acid
Other names
(S)-Kynurenine
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
DrugBank
MeSH Kynurenine
UNII
Properties
C10H12N2O3
Molar mass 208.217 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Infobox references
Tracking categories (test):

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]

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

References

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  3. "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. doi:10.1073/pnas.1014465107. PMID 21041655. Bibcode2010PNAS..10719961N. 
  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" (in en). The Journal of Physical Chemistry B 113 (14): 4953–4962. doi:10.1021/jp900541b. ISSN 1520-6106. https://pubs.acs.org/doi/10.1021/jp900541b. 
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  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. doi:10.1016/0014-5793(94)00601-6. ISSN 0014-5793. https://www.sciencedirect.com/science/article/pii/0014579394006016. 
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  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. ISSN 0146-0404. PMID 11133868. https://pubmed.ncbi.nlm.nih.gov/11133868. 
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  14. 14.0 14.1 Bartoli, F; Misiak, B; Callovini, T; Cavaleri, D; Cioni, RM; Crocamo, C; Savitz, JB; Carrà, G (19 October 2020). "The kynurenine pathway in bipolar disorder: a meta-analysis on the peripheral blood levels of tryptophan and related metabolites.". Molecular Psychiatry 26 (7): 3419–3429. doi:10.1038/s41380-020-00913-1. PMID 33077852. 
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  19. 19.0 19.1 "Plasma kynurenine and related measures in tic disorder patients". European Child & Adolescent Psychiatry 16: 71–7. 2007. doi:10.1007/s00787-007-1009-1. PMID 17665285. 
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  21. Kynureninase, European Bioinformatics Institute
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