Kynurenine pathway

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Kynurenine pathway
Source: Mellor AL, Lemos H and Huang L (2017). Front. Immunol.8:1360.

The kynurenine pathway or tryptophan kynurenine pathway is the primary route for metabolizing the essential amino acid tryptophan in humans and other mammals[1] in order to generate cellular energy in the form of nicotinamide adenine dinucleotide (NAD+).[2][3]

If the kynurenine pathway becomes dysregulated or overactive, it can activate the immune system and result in a build-up of potentially neurotoxic compounds in the body.[3]

Function[edit | edit source]

Schematic representation of the kynurenine pathway.
Key: IDO1: indoleamine 2,3-dioxygenase 1; IDO2: indoleamine 2,3-dioxygenase 2; TDO2: tryptophan 2,3-dioxygenase; TPH1: Tryptophan hydroxylase 1; TPH2: Tryptophan hydroxylase 2; AFMID: arylformamidase; KMO: kynurenine 3-monooxygenase; CCBL1: kynurenine aminotransferase I; AADAT: kynurenine aminotransferase II; CCBL2: kynurenine aminotransferase III; KYNU: kynureninase; HAAO: 3-hydroxyanthranilate 3,4-dioxygenase; QPRT, quinolinate phosphoribosyl transferase; ACMSD: aminocarboxymuconate semialdehyde decarboxylase. Source: Favennec et al. (2016). PLoS ONE 11(6): e0158051

ME/CFS[edit | edit source]

The metabolic trap hypothesis suggests that a metabolic problem exists in one or more areas of a person with ME/CFS, with a defect in the IDO2 enzyme of the tryptophan kynurenine pathway being identified as a possible metabolic trap.

In April 2020, the Open Medicine Foundation announced a pilot treatment trial of kynurenine for ME/CFS patients.[4]

See also
Metabolic trap.

Notable studies[edit | edit source]

  • 2022, Post-acute COVID-19 cognitive impairment and decline uniquely associate with kynurenine pathway activation: a longitudinal observational study[5] - (Full text)- not yet peer reviewed
  • 2022, Could the kynurenine pathway be the key missing piece of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) complex puzzle?[6] - (Full text)
  • 2021, Role of Kynurenine Pathway in Oxidative Stress during Neurodegenerative Disorders[7] - (Full text)
  • 2021, Kynurenine Pathway of Tryptophan Metabolism in Migraine and Functional Gastrointestinal Disorders[8] - (Full text)
  • 2021, Incomplete Systemic Recovery and Metabolic Phenoreversion in Post-Acute-Phase Nonhospitalized COVID-19 Patients: Implications for Assessment of Post-Acute COVID-19 Syndrome[9] - (Full text)
  • 2021, Co-players in chronic pain: Neuroinflammation and the tryptophan-kynurenine metabolic pathway[10] - (Full text)
  • 2021, Tryptophan Metabolites, Cytokines, and Fatty Acid Binding Protein 2 in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome[11] - (Full text)
  • 2021, Kynurenine Metabolites and Ratios Differ Between Chronic Fatigue Syndrome, Fibromyalgia, and Healthy Controls[12] - (Full text)
  • 2021, Increased Kynurenine Indicates a Fatal Course of COVID-19[13] - (Full text)
  • 2021, A map of metabolic phenotypes in patients with myalgic encephalomyelitis/chronic fatigue syndrome[14] - (Full text)
  • 2020, The kynurenine pathway: a finger in every pie[2] - (Full text)
  • 2020, IDO and kynurenine metabolites in peripheral and CNS disorders[15] - (Full text)
  • 2020, Chronic fatigue and depression due to multiple sclerosis: Immune-inflammatory pathways, tryptophan catabolites and the gut-brain axis as possible shared pathways[16] - (Full text)
  • 2020, Accumulation of kynurenine elevates oxidative stress and alters microRNA profile in human bone marrow stromal cells[17] - (Full text)
  • 2019, The plasma [kynurenine]/[tryptophan] ratio and indoleamine 2, 3-dioxygenase: time for appraisal[18] - (Full text)
  • 2019, The IDO Metabolic Trap Hypothesis for the Etiology of ME/CFS[19] - (Full text)
  • 2018, Tryptophan-Kynurenine Metabolites in Exercise and Mental Health[20] - (Chapter)
  • 2017, Kynurenines: Tryptophan's metabolites in exercise, inflammation, and mental health[21] - (Abstract)
  • 2017, Indoleamine 2,3-Dioxygenase and Tolerance: Where Are We Now?[22] - (Full text)
  • 2017, The Kynurenine Pathway As a Novel Link between Allergy and the Gut Microbiome[23] - (Full text)
  • 2015, What is the tryptophan kynurenine pathway and why is it important to neurotherapeutics?[3] - (Full text)
  • 2014, Activation of the kynurenine pathway in the acute phase of stroke and its role in fatigue and depression following stroke[24] - (Full text)
  • 2004, Heterogeneity of serum tryptophan concentration and availability to the brain in patients with the chronic fatigue syndrome[25] - (Full text)
  • 1992, Quinolinic acid and kynurenine pathway metabolism in inflammatory and non-inflammatory neurological disease[26] - (Full text)

See also[edit | edit source]

Learn more[edit | edit source]

References[edit | edit source]

  1. ↑ Chen, Yiquan; Guillemin, Gilles J. (January 8, 2009). "Kynurenine Pathway Metabolites in Humans: Disease and Healthy States". International Journal of Tryptophan Research : IJTR. 2: 1–19. ISSN 1178-6469. PMC 3195227. PMID 22084578.
  2. ↑ 2.0 2.1 Savitz, Jonathan (January 2020). "The kynurenine pathway: a finger in every pie". Molecular Psychiatry. 25 (1): 131–147. doi:10.1038/s41380-019-0414-4. ISSN 1476-5578.
  3. ↑ 3.0 3.1 3.2 Davis, I.; Liu, A. (July 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 1473-7175. PMID 26004930.
  4. ↑ Open Medicine Foundation (April 26, 2020). "Kynurenine Clinical Trial for ME/CFS". Open Medicine Foundation. Retrieved May 1, 2020.
  5. ↑ Cysique, Lucette A.; Jakabek, David; Bracken, Sophia G.; Allen-Davidian, Yasmin; Heng, Benjamin; Chow, Sharron; Dehhaghi, Mona; Pires, Ananda Staats; Darley, David R.; Byrne, Anthony; Phetsouphanh, Chansavath (June 7, 2022). "Post-acute COVID-19 cognitive impairment and decline uniquely associate with kynurenine pathway activation: a longitudinal observational study". Medrxiv: 2022.06.07.22276020. doi:10.1101/2022.06.07.22276020v1.
  6. ↑ Kavyani, Bahar; Lidbury, Brett A.; Schloeffel, Richard; Fisher, Paul R.; Missailidis, Daniel; Annesley, Sarah J.; Dehhaghi, Mona; Heng, Benjamin; Guillemin, Gilles J. (July 11, 2022). "Could the kynurenine pathway be the key missing piece of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) complex puzzle?". Cellular and Molecular Life Sciences. 79 (8): 412. doi:10.1007/s00018-022-04380-5. ISSN 1420-9071. PMC 9276562. PMID 35821534.
  7. ↑ Mor, Adrian; Tankiewicz-Kwedlo, Anna; Krupa, Anna; Pawlak, Dariusz (June 26, 2021). "Role of Kynurenine Pathway in Oxidative Stress during Neurodegenerative Disorders". Cells. 10 (7): 1603. doi:10.3390/cells10071603. ISSN 2073-4409. PMC 8306609. PMID 34206739.
  8. ↑ Fila, Michal; Chojnacki, Jan; Pawlowska, Elzbieta; Szczepanska, Joanna; Chojnacki, Cezary; Blasiak, Janusz (September 20, 2021). "Kynurenine Pathway of Tryptophan Metabolism in Migraine and Functional Gastrointestinal Disorders". International Journal of Molecular Sciences. 22 (18): 10134. doi:10.3390/ijms221810134. ISSN 1422-0067. PMC 8469852. PMID 34576297.
  9. ↑ Holmes, Elaine; Wist, Julien; Masuda, Reika; Lodge, Samantha; Nitschke, Philipp; Kimhofer, Torben; Loo, Ruey Leng; Begum, Sofina; Boughton, Berin; Yang, Rongchang; Morillon, Aude-Claire (June 4, 2021). "Incomplete Systemic Recovery and Metabolic Phenoreversion in Post-Acute-Phase Nonhospitalized COVID-19 Patients: Implications for Assessment of Post-Acute COVID-19 Syndrome". Journal of Proteome Research. 20 (6): 3315–3329. doi:10.1021/acs.jproteome.1c00224. ISSN 1535-3893. PMC 8147448. PMID 34009992.
  10. ↑ Tanaka, Masaru; Török, Nóra; Tóth, Fanni; Szabó, Ágnes; Vécsei, László (July 26, 2021). "Co-Players in Chronic Pain: Neuroinflammation and the Tryptophan-Kynurenine Metabolic Pathway". Biomedicines. 9 (8): 897. doi:10.3390/biomedicines9080897. ISSN 2227-9059. PMC 8389666. PMID 34440101.
  11. ↑ Simonato, Manuela; Dall’Acqua, Stefano; Zilli, Caterina; Sut, Stefania; Tenconi, Romano; Gallo, Nicoletta; Sfriso, Paolo; Sartori, Leonardo; Cavallin, Francesco; Fiocco, Ugo; Cogo, Paola (November 19, 2021). "Tryptophan Metabolites, Cytokines, and Fatty Acid Binding Protein 2 in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome". Biomedicines. 9 (11): 1724. doi:10.3390/biomedicines9111724. ISSN 2227-9059. PMC 8615774. PMID 34829952.
  12. ↑ Groven, Nina; Reitan, Solveig Klæbo; Fors, Egil Andreas; Guzey, Ismail Cuneyt (September 1, 2021). "Kynurenine metabolites and ratios differ between Chronic Fatigue Syndrome, Fibromyalgia, and healthy controls". Psychoneuroendocrinology. 131: 105287. doi:10.1016/j.psyneuen.2021.105287. ISSN 0306-4530.
  13. ↑ Mangge, Harald; Herrmann, Markus; Meinitzer, Andreas; Pailer, Sabine; Curcic, Pero; Sloup, Zdenka; Holter, Magdalena; Prüller, Florian (December 7, 2021). "Increased Kynurenine Indicates a Fatal Course of COVID-19". Antioxidants (Basel, Switzerland). 10 (12): 1960. doi:10.3390/antiox10121960. ISSN 2076-3921. PMID 34943063.
  14. ↑ Hoel, Fredrik; Hoel, August; Pettersen, Ina K.N.; Rekeland, Ingrid G.; Risa, Kristin; Alme, Kine; Sørland, Kari; Fosså, Alexander; Lien, Katarina; Herder, Ingrid; Thürmer, Hanne L. (2021). "A map of metabolic phenotypes in patients with myalgic encephalomyelitis/chronic fatigue syndrome". JCI Insight. 6 (16): e149217. doi:10.1172/jci.insight.149217. ISSN 2379-3708. PMC 8409979. PMID 34423789.
  15. ↑ Huang, Yi-Shu; Ogbechi, Joy; Clanchy, Felix I.; Williams, Richard O.; Stone, Trevor W. (2020). "IDO and Kynurenine Metabolites in Peripheral and CNS Disorders". Frontiers in Immunology. 11: 388. doi:10.3389/fimmu.2020.00388. ISSN 1664-3224.
  16. ↑ Ormstad, Heidi; Simonsen, Cecilia Smith; Broch, Line; Maes, Dr Michael; Anderson, George; Celius, Elisabeth G. (November 2020). "Chronic fatigue and depression due to multiple sclerosis: Immune-inflammatory pathways, tryptophan catabolites and the gut-brain axis as possible shared pathways". Multiple Sclerosis and Related Disorders. 46: 102533. doi:10.1016/j.msard.2020.102533. ISSN 2211-0356. PMID 33010585.
  17. ↑ Dalton, Sherwood; Smith, Kathryn; Singh, Kanwar; Kaiser, Helen; Kolhe, Ravindra; Mondal, Ashis K.; Khayrullin, Andrew; Isales, Carlos M.; Hamrick, Mark W.; Hill, William D.; Fulzele, Sadanand (February 1, 2020). "Accumulation of kynurenine elevates oxidative stress and alters microRNA profile in human bone marrow stromal cells". Experimental Gerontology. 130: 110800. doi:10.1016/j.exger.2019.110800. ISSN 0531-5565.
  18. ↑ Badawy, Abdulla A-B; Guillemin, Gilles (January 1, 2019). "The Plasma [Kynurenine]/[Tryptophan] Ratio and Indoleamine 2,3-Dioxygenase: Time for Appraisal". International Journal of Tryptophan Research. 12: 1178646919868978. doi:10.1177/1178646919868978. ISSN 1178-6469. PMC 6710706. PMID 31488951.
  19. ↑ Phair, Robert D.; Davis, Ronald W.; Kashi, Alex A. (2019). "The IDO Metabolic Trap Hypothesis for the Etiology of ME/CFS". Diagnostics. 9 (3): 82. doi:10.3390/diagnostics9030082.
  20. ↑ Valente-Silva, Paula; Ruas, Jorge Lira (2017). "Tryptophan-Kynurenine Metabolites in Exercise and Mental Health". In Spiegelman, Bruce (ed.). Hormones, Metabolism and the Benefits of Exercise. Cham (CH): Springer. ISBN 978-3-319-72789-9. PMID 31314466.
  21. ↑ Cervenka, Igor; Agudelo, Leandro Z.; Ruas, Jorge L. (July 28, 2017). "Kynurenines: Tryptophan's metabolites in exercise, inflammation, and mental health". Science. 357 (6349): eaaf9794. doi:10.1126/science.aaf9794.
  22. ↑ Mellor, Andrew L.; Lemos, Henrique; Huang, Lei (2017). "Indoleamine 2,3-Dioxygenase and Tolerance: Where Are We Now?". Frontiers in Immunology. 8: 1360. doi:10.3389/fimmu.2017.01360. ISSN 1664-3224.
  23. ↑ Van der Leek, Aaron P.; Yanishevsky, Yarden; Kozyrskyj, Anita L. (2017). "The Kynurenine Pathway As a Novel Link between Allergy and the Gut Microbiome". Frontiers in Immunology. 8: 1374. doi:10.3389/fimmu.2017.01374. ISSN 1664-3224. PMC 5681735. PMID 29163472.
  24. ↑ Ormstad, Heidi; Verkerk, Robert; Amthor, Karl-Friedrich; Sandvik, Leiv (2014). "Activation of the kynurenine pathway in the acute phase of stroke and its role in fatigue and depression following stroke" (PDF). Journal of molecular neuroscience: MN. 54 (2): 181–187. doi:10.1007/s12031-014-0272-0. ISSN 1559-1166. PMID 24664436.
  25. ↑ Badawy, Abdulla A.-B.; Morgan, Christopher J.; Llewelyn, Meirion B.; Albuquerque, Selwyn R.J.; Farmer, Anne (July 2005). "Heterogeneity of serum tryptophan concentration and availability to the brain in patients with the chronic fatigue syndrome". Journal of Psychopharmacology (Oxford, England). 19 (4): 385–391. doi:10.1177/0269881105053293. ISSN 0269-8811. PMID 15982993.
  26. ↑ Heyes, M.P.; Saito, K.; Crowley, J.S.; Davis, L.E.; Demitrack, M.A.; Der, M.; Dilling, L.A.; Elia, J.; Kruesi, M.J. (October 1992). "Quinolinic acid and kynurenine pathway metabolism in inflammatory and non-inflammatory neurological disease" (PDF). Brain: A Journal of Neurology. 115 (Pt 5): 1249–1273. doi:10.1093/brain/115.5.1249. ISSN 0006-8950. PMID 1422788.
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