Biology:Kynurenine pathway

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Short description: Metabolic pathway that produces the NAD coenzyme

thumb|400px|The kynurenine pathway

The kynurenine pathway is a metabolic pathway leading to the production of nicotinamide adenine dinucleotide (NAD+).[1] Metabolites involved in the kynurenine pathway include tryptophan, kynurenine, kynurenic acid, xanthurenic acid, quinolinic acid, and 3-hydroxykynurenine.[2] [3] The kynurenine pathway is responsible for total catabolization of tryptophan about 95%.[4] Disruption in the pathway is associated with certain genetic and psychiatric disorders.[5][2][6][7][8]

Kynurenine pathway dysfunction

Disorders affecting the kynurenine pathway may be primary (of genetic origin) or secondary (due to inflammatory conditions).[9] Peripheral inflammation can lead to a build up of kynurenine in the brain, and this is associated with major depressive disorder,[5][6] bipolar disorder,[1] [5][2][8] and schizophrenia.[5][7][6] Dysfunction of the pathway not only causes increase in amounts of metabolites such as quinolinic acid and kynurenic acid but also affects synthesis of serotonin and melatonin.[10] Kynurenine clearance in exercised muscle cells can suppress the build up in the brain.[11][12]

Hydroxykynureninuria

Also known as kynureninase deficiency, this extremely rare inherited disorder is caused by the defective enzyme kynureninase which leads to a block in the pathway from tryptophan to niacin (nicotinic acid). As a result, tryptophan is no longer a source of niacin, hence leading to pellagra (niacin deficiency). Both B6-responsive and B6-unresponsive forms are known. Patients with this disorder excrete excessive amounts of xanthurenic acid, kynurenic acid, 3-hydroxykynurenine, and kynurenine after tryptophan loading and are said to suffer from tachycardia, irregular breathing, arterial hypotension, cerebellar ataxia, developmental retardation, coma, renal tubular dysfunction, renal or metabolic acidosis, and even death. The only biochemical abnormality noted in affected patients was a massive hyperkynureninuria, seen only during periods of coma or after intravenous protein loading. This disturbance was temporarily corrected by large doses of vitamin B6. The activity of kynureninase in the liver was markedly reduced. The activity was appreciably restored by the addition of pyridoxal phosphate.[13][14][15][16]

Acquired and inherited enzyme deficiencies

Downregulation of kynurenine 3-monooxygenase (KMO) can be caused by genetic polymorphisms, cytokines, or both.[17][18] KMO deficiency leads to an accumulation of kynurenine and to a shift within the tryptophan metabolic pathway towards kynurenic acid and anthranilic acid.[19][20][21][22][23][24]

Deficiencies of one or more enzymes on the kynurenine pathway leads to an accumulation of intermediate metabolic products which can cause effects depending on their concentration, function and their inter-relation with other metabolic products.[19] For example, kynurenine 3-monooxygenase deficiency is associated with disorders of the brain (such as schizophrenia and tic disorders) and of the liver.[22][20][21][23][24] The mechanism behind this observation is typically a blockade or bottleneck situation at one or more enzymes on the kynurenine pathway due to the effects of indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO) and/or due to genetic polymorphisms afflicting the particular genes.[19][18][25][21] 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, for example:[26]

Research

Research into roles of the kynurenine pathway in human physiology is ongoing.[1]

Neurodegenerative diseases and mental disorders

Scientists are investigating the role of dysregulation of this pathway in aging, neurodegenerative diseases, mental disorders, somatic symptom disorders, and chronic fatigue syndrome (CFS).[29][30][31][32][2][1]

Kynurenine/tryptophan ratio

Changes in the ratio of kynurenine versus tryptophan are reported for many diseases like arthritis, HIV/AIDS, neuropsychiatric disorders,[1][6][2] cancer and inflammations.[33][34][35][36] The kynurenin/tryptophan is also an indicator for the activity of indoleamine 2,3-dioxygenase (IDO).[37][38]

Methods

Kynurenine metabolites can be quantified using liquid chromatography coupled to mass spectrometry.[39]

Related substrates

In some species, the kynurenine pathway also processes 6-bromotryptophan, leading to the analogous series of brominated metabolites. These and subsequent derivatives are believed to be responsible for the biofluorescence observed in the skin of the swell shark and the chain catshark.[40]

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 Bartoli, F; Cioni, RM; Cavaleri, D; Callovini, T; Crocamo, C; Misiak, B; Savitz, JB; Carrà, G (11 November 2022). "The association of kynurenine pathway metabolites with symptom severity and clinical features of bipolar disorder: An overview.". European Psychiatry 65 (1): e82. doi:10.1192/j.eurpsy.2022.2340. PMID 36366795. 
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 Bartoli, F; Misiak, B; Callovini, T; Cavaleri, D; Cioni, RM; Crocamo, C; Savitz, JB; Carrà, G (July 2021). "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. 
  3. ↑ Savitz, J (25 January 2020). "The kynurenine pathway: a finger in every pie.". Molecular Psychiatry 25 (1): 131–147. doi:10.1038/s41380-019-0414-4. PMID 30980044. 
  4. ↑ Thomas, Sunil; Laury-Kleintop, Lisa; Prendergast, George C. (2019-01-01), "Chapter Twelve - Reliable detection of indoleamine 2,3 dioxygenase-1 in murine cells and tissues", in Galluzzi, Lorenzo; Rudqvist, Nils-Petter (in en), Tumor Immunology and Immunotherapy – Molecular Methods, Methods in Enzymology, 629, Academic Press, pp. 219–233, doi:10.1016/bs.mie.2019.08.008, PMID 31727242, https://www.sciencedirect.com/science/article/pii/S0076687919303532, retrieved 2022-04-12 
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 5.6 5.7 Marx, Wolfgang; McGuinness, Amelia J.; Rocks, Tetyana; Ruusunen, Anu; Cleminson, Jasmine; Walker, Adam J.; Gomes-da-Costa, Susana; Lane, Melissa et al. (August 2021). "The kynurenine pathway in major depressive disorder, bipolar disorder, and schizophrenia: a meta-analysis of 101 studies" (in en). Molecular Psychiatry 26 (8): 4158–4178. doi:10.1038/s41380-020-00951-9. ISSN 1359-4184. PMID 33230205. https://www.nature.com/articles/s41380-020-00951-9. 
  6. ↑ 6.0 6.1 6.2 6.3 6.4 Bartoli, F; Cioni, RM; Callovini, T; Cavaleri, D; Crocamo, C; Carrà, G (17 May 2021). "The kynurenine pathway in schizophrenia and other mental disorders: Insight from meta-analyses on the peripheral blood levels of tryptophan and related metabolites.". Schizophrenia Research 232: 61–62. doi:10.1016/j.schres.2021.04.008. PMID 34015557. 
  7. ↑ 7.0 7.1 7.2 Morrens, Manuel; De Picker, Livia; Kampen, Jarl K.; Coppens, Violette (September 2020). "Blood-based kynurenine pathway alterations in schizophrenia spectrum disorders: A meta-analysis". Schizophrenia Research 223: 43–52. doi:10.1016/j.schres.2020.09.007. ISSN 1573-2509. PMID 32981827. https://pubmed.ncbi.nlm.nih.gov/32981827. 
  8. ↑ 8.0 8.1 8.2 8.3 Arnone, Danilo; Saraykar, Smita; Salem, Haitham; Teixeira, Antonio L.; Dantzer, Robert; Selvaraj, Sudhakar (September 2018). "Role of Kynurenine pathway and its metabolites in mood disorders: A systematic review and meta-analysis of clinical studies". Neuroscience and Biobehavioral Reviews 92: 477–485. doi:10.1016/j.neubiorev.2018.05.031. ISSN 1873-7528. PMID 29940237. 
  9. ↑ Davis, Ian; Liu, Aimin (2015). "What is the tryptophan kynurenine pathway and why is it important to neurotherapeutics?". Expert Review of Neurotherapeutics 15 (7): 719–721. doi:10.1586/14737175.2015.1049999. ISSN 1744-8360. PMID 26004930. 
  10. ↑ Zoga, Margarita; Oulis, Panagiotis; Chatzipanagiotou, Stylianos; Masdrakis, Vasilios G.; Pliatsika, Paraskevi; Boufidou, Fotini; Foteli, Stefania; Soldatos, Constantin R. et al. (July 2014). "Indoleamine 2,3-dioxygenase and immune changes under antidepressive treatment in major depression in females". In Vivo (Athens, Greece) 28 (4): 633–638. ISSN 1791-7549. PMID 24982234. https://pubmed.ncbi.nlm.nih.gov/24982234/. 
  11. ↑ Pedersen, BK (July 2019). "Physical activity and muscle-brain crosstalk.". Nature Reviews. Endocrinology 15 (7): 383–392. doi:10.1038/s41574-019-0174-x. PMID 30837717. 
  12. ↑ Cervenka, I; Agudelo, LZ; Ruas, JL (28 July 2017). "Kynurenines: Tryptophan's metabolites in exercise, inflammation, and mental health.". Science 357 (6349): eaaf9794. doi:10.1126/science.aaf9794. PMID 28751584. 
  13. ↑ "Congenital non-progressive encephalopathy and deafness with intermittent episodes of coma and hyperkynureninuria". Journal of Inherited Metabolic Disease 19 (1): 25–30. 1996. doi:10.1007/BF01799345. PMID 8830173. 
  14. ↑ "Hydroxykynureninuria". American Journal of Diseases of Children 113 (1): 77–80. January 1967. doi:10.1001/archpedi.1967.02090160127016. PMID 6015911. 
  15. ↑ "Lethal familial pellagra-like skin lesion associated with neurologic and developmental impairment and the development of cataracts". Pediatrics 76 (5): 787–793. November 1985. doi:10.1542/peds.76.5.787. PMID 4058988. 
  16. ↑ "Vitamin B6 dependent xanthurenic aciduria". The Tohoku Journal of Experimental Medicine 93 (2): 115–124. October 1967. doi:10.1620/tjem.93.115. PMID 5586569. 
  17. ↑ "Neurobiochemie und Psychopharmakologie" (in de). Klinikums der Universität München. http://www.klinikum.uni-muenchen.de/Institut-fuer-Laboratoriumsmedizin/de/forschung/neurobiochemie/index.html. 
  18. ↑ 18.0 18.1 "Inflammatory biomarkers and depression". Neurotoxicity Research 19 (2): 308–318. February 2011. doi:10.1007/s12640-010-9210-2. PMID 20658274. 
  19. ↑ 19.0 19.1 19.2 "Downregulated kynurenine 3-monooxygenase gene expression and enzyme activity in schizophrenia and genetic association with schizophrenia endophenotypes". Archives of General Psychiatry 68 (7): 665–674. July 2011. doi:10.1001/archgenpsychiatry.2011.71. PMID 21727251. 
  20. ↑ 20.0 20.1 "Kynurenine 3-monooxygenase polymorphisms: relevance for kynurenic acid synthesis in patients with schizophrenia and healthy controls". Journal of Psychiatry & Neuroscience 37 (1): 53–57. January 2012. doi:10.1503/jpn.100175. PMID 21693093. 
  21. ↑ 21.0 21.1 21.2 "Kynurenines in CNS disease: regulation by inflammatory cytokines". Frontiers in Neuroscience 8: 12. 2014. doi:10.3389/fnins.2014.00012. PMID 24567701. 
  22. ↑ 22.0 22.1 "Plasma kynurenine and related measures in tic disorder patients". European Child & Adolescent Psychiatry 16 (Suppl 1): 71–77. June 2007. doi:10.1007/s00787-007-1009-1. PMID 17665285. 
  23. ↑ 23.0 23.1 "Identification of metabolites, clinical chemistry markers and transcripts associated with hepatotoxicity". PLOS ONE 9 (5): e97249. 2014. doi:10.1371/journal.pone.0097249. PMID 24836604. Bibcode: 2014PLoSO...997249B. 
  24. ↑ 24.0 24.1 "Fatty liver induced by injection of L-tryptophan". Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism 144 (2): 233–241. October 1967. doi:10.1016/0005-2760(67)90153-1. PMID 4168935. 
  25. ↑ "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". Life Sciences 71 (16): 1837–1848. September 2002. doi:10.1016/s0024-3205(02)01853-2. PMID 12175700. 
  26. ↑ "Kynurenines in the CNS: from endogenous obscurity to therapeutic importance". Progress in Neurobiology 64 (2): 185–218. June 2001. doi:10.1016/s0301-0082(00)00032-0. PMID 11240212. 
  27. ↑ Template:Cite medRxiv
  28. ↑ "Long COVID: major findings, mechanisms and recommendations". Nature Reviews Microbiology 21 (3): 133-146. 2023. doi:10.1038/s41579-022-00846-2. PMID 36639608. 
  29. ↑ Dogrul, Bekir Nihat (2022-03-01). "Indolamine 2,3-dioxygenase (IDO) inhibitors as a potential treatment for somatic symptoms" (in en). Medical Hypotheses 160: 110777. doi:10.1016/j.mehy.2022.110777. ISSN 0306-9877. https://www.sciencedirect.com/science/article/pii/S0306987722000172. 
  30. ↑ Blankfield, Adele (2013-07-21). "Article Commentary: Kynurenine Pathway Pathologies: Do Nicotinamide and Other Pathway Co-Factors have a Therapeutic Role in Reduction of Symptom Severity, Including Chronic Fatigue Syndrome (CFS) and Fibromyalgia (FM)" (in en). International Journal of Tryptophan Research 6s1 (Suppl 1): 39–45. doi:10.4137/IJTR.S11193. PMID 23922501. 
  31. ↑ "Tryptophan metabolism: entering the field of aging and age-related pathologies". Trends in Molecular Medicine 19 (6): 336–344. June 2013. doi:10.1016/j.molmed.2013.02.007. PMID 23562344. 
  32. ↑ "Kynurenines in the mammalian brain: when physiology meets pathology". Nature Reviews. Neuroscience 13 (7): 465–477. July 2012. doi:10.1038/nrn3257. PMID 22678511. 
  33. ↑ "Serum kynurenine-to-tryptophan ratio increases with progressive disease in HIV-infected patients". Clinical Chemistry 44 (4): 858–862. April 1998. doi:10.1093/clinchem/44.4.858. PMID 9554499. 
  34. ↑ "Increased degradation of tryptophan in blood of patients with rheumatoid arthritis". The Journal of Rheumatology 30 (9): 1935–1939. September 2003. PMID 12966593. 
  35. ↑ "Increased serum kynurenine/tryptophan ratio correlates with disease progression in lung cancer". Lung Cancer (Amsterdam, Netherlands) 67 (3): 361–365. March 2010. doi:10.1016/j.lungcan.2009.05.001. PMID 19487045. 
  36. ↑ Millischer, Vincent; Heinzl, Matthias; Faka, Anthi; Resl, Michael; Trepci, Ada; Klammer, Carmen; Egger, Margot; Dieplinger, Benjamin et al. (2021-07-17). "Intravenous administration of LPS activates the kynurenine pathway in healthy male human subjects: a prospective placebo-controlled cross-over trial". Journal of Neuroinflammation 18 (1): 158. doi:10.1186/s12974-021-02196-x. ISSN 1742-2094. PMID 34273987. 
  37. ↑ "Simultaneous measurement of serum tryptophan and kynurenine by HPLC". Clinical Chemistry 43 (12): 2424–2426. December 1997. doi:10.1093/clinchem/43.12.2424. PMID 9439467. 
  38. ↑ "Decreased serum tryptophan in patients with HIV-1 infection correlates with increased serum neopterin and with neurologic/psychiatric symptoms". Journal of Acquired Immune Deficiency Syndromes 3 (9): 873–876. 1990. PMID 2166783. 
  39. ↑ Midttun, Øivind; Hustad, Steinar; Ueland, Per M. (2009). "Quantitative profiling of biomarkers related to B-vitamin status, tryptophan metabolism and inflammation in human plasma by liquid chromatography/tandem mass spectrometry" (in en). Rapid Communications in Mass Spectrometry 23 (9): 1371–1379. doi:10.1002/rcm.4013. ISSN 1097-0231. PMID 19337982. Bibcode: 2009RCMS...23.1371M. https://onlinelibrary.wiley.com/doi/abs/10.1002/rcm.4013. 
  40. ↑ Park, Hyun Bong; Lam, Yick Chong; Gaffney, Jean P.; Weaver, James C.; Krivoshik, Sara Rose; Hamchand, Randy; Pieribone, Vincent; Gruber, David F. et al. (2019). "Bright Green Biofluorescence in Sharks Derives from Bromo-Kynurenine Metabolism". iScience 19: 1291–1336. doi:10.1016/j.isci.2019.07.019. PMID 31402257. Bibcode: 2019iSci...19.1291P. 



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