Kynurenine pathway

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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]

Notable studies[edit | edit source]

  • 1992, Quinolinic acid and kynurenine pathway metabolism in inflammatory and non-inflammatory neurological disease[5] - (Full text)
  • 2004, Heterogeneity of serum tryptophan concentration and availability to the brain in patients with the chronic fatigue syndrome[6] - (Full text)
  • 2014, Activation of the kynurenine pathway in the acute phase of stroke and its role in fatigue and depression following stroke[7] - (Full text)
  • 2015, What is the tryptophan kynurenine pathway and why is it important to neurotherapeutics?[3] - (Full text)
  • 2017, Indoleamine 2,3-Dioxygenase and Tolerance: Where Are We Now?[8] - (Full text)
  • 2017, Kynurenines: Tryptophan's metabolites in exercise, inflammation, and mental health[9] - (Abstract)
  • 2017, The Kynurenine Pathway As a Novel Link between Allergy and the Gut Microbiome[10] - (Full text)
  • 2018, Tryptophan-Kynurenine Metabolites in Exercise and Mental Health[11] - (Chapter)
  • 2019, The IDO Metabolic Trap Hypothesis for the Etiology of ME/CFS[12] - (Full text)
  • 2019, The plasma [kynurenine]/[tryptophan] ratio and indoleamine 2, 3-dioxygenase: time for appraisal[13] - (Full text)
  • 2020, Accumulation of kynurenine elevates oxidative stress and alters microRNA profile in human bone marrow stromal cells[14] - (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[15] - (Full text)
  • 2020, IDO and kynurenine metabolites in peripheral and CNS disorders[16] - (Full text)
  • 2020, The kynurenine pathway: a finger in every pie[2] - (Full text)
  • 2021, A map of metabolic phenotypes in patients with myalgic encephalomyelitis/chronic fatigue syndrome[17] - (Full text)
  • 2021, Co-players in chronic pain: Neuroinflammation and the tryptophan-kynurenine metabolic pathway[18] - (Full text)
  • 2021, Kynurenine Metabolites and Ratios Differ Between Chronic Fatigue Syndrome, Fibromyalgia, and Healthy Controls[19] - (Full text)
  • 2021, Kynurenine Pathway of Tryptophan Metabolism in Migraine and Functional Gastrointestinal Disorders[20] - (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[21] - (Full text)
  • 2021, Increased Kynurenine Indicates a Fatal Course of COVID-19[22] - (Full text)
  • 2021, Role of Kynurenine Pathway in Oxidative Stress during Neurodegenerative Disorders[23] - (Full text)
  • 2021, Tryptophan Metabolites, Cytokines, and Fatty Acid Binding Protein 2 in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome[24] - (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. 2.02.1 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. 3.03.13.2 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. 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.
  6. 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.
  7. 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.
  8. 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.
  9. 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.
  10. 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.
  11. 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.
  12. 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.
  13. 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.
  14. 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.
  15. 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.
  16. 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.
  17. 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.
  18. 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.
  19. 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.
  20. 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.
  21. 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.
  22. 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.
  23. 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.
  24. 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.

indoleamine (IDO) - any derivatives of an indole (e.g., serotonin, tryptophan) that contain an amine group

enzyme a substance produced by a living organism which acts as a catalyst to bring about a specific biochemical reaction.

metabolic trap hypothesis An hypothesis which proposes that the normal metabolic functioning of the cell has become "trapped" in an abnormal state, which may lead to body-wide symptoms.

serum The clear yellowish fluid that remains from blood plasma after clotting factors have been removed by clot formation. (Blood plasma is simply blood that has had its blood cells removed.)

metabolite A chemical compound produced by, or involved in, metabolism. The term is often used to refer to the degradation products of drugs in the body.

microbiome The full collection of microscopic organisms (especially bacteria and fungi) which are present in a particular environment, particularly inside the human body.

metabolite A chemical compound produced by, or involved in, metabolism. The term is often used to refer to the degradation products of drugs in the body.

indoleamine (IDO) - any derivatives of an indole (e.g., serotonin, tryptophan) that contain an amine group

indole (IDO) - a signalling molecule produced by bacteria as a result of metabolising tryptophan, found in the intestines

metabolic trap hypothesis An hypothesis which proposes that the normal metabolic functioning of the cell has become "trapped" in an abnormal state, which may lead to body-wide symptoms.

etiology The cause of origin, especially of a disease.

central nervous system (CNS) - One of the two parts of the human nervous system, the other part being the peripheral nervous system. The central nervous system consists of the brain and spinal cord, while the peripheral nervous system consists of nerves that travel from the central nervous system into the various organs and tissues of the body.

cytokine any class of immunoregulatory proteins secreted by cells, especially immune cells. Cytokines are small proteins important in cell signaling that modulate the immune system. (Learn more: me-pedia.org)

myalgic encephalomyelitis (M.E.) - A disease often marked by neurological symptoms, but fatigue is sometimes a symptom as well. Some diagnostic criteria distinguish it from chronic fatigue syndrome, while other diagnostic criteria consider it to be a synonym for chronic fatigue syndrome. A defining characteristic of ME is post-exertional malaise (PEM), or post-exertional neuroimmune exhaustion (PENE), which is a notable exacerbation of symptoms brought on by small exertions. PEM can last for days or weeks. Symptoms can include cognitive impairments, muscle pain (myalgia), trouble remaining upright (orthostatic intolerance), sleep abnormalities, and gastro-intestinal impairments, among others. An estimated 25% of those suffering from ME are housebound or bedbound. The World Health Organization (WHO) classifies ME as a neurological disease.

The information provided at this site is not intended to diagnose or treat any illness.
From MEpedia, a crowd-sourced encyclopedia of ME and CFS science and history.