Kynurenine pathway

The kynurenine pathway is a metabolic pathway leading to the production of nicotinamide adenine dinucleotide (NAD+), as well as other active metabolites, from the degradation of tryptophan, an essential amino acid. Disruption in the pathway is associated with certain genetic disorders.

The kynurenine pathway

Kynurenine pathway dysfunction

Disorders affecting the kynurenine pathway may be primary (of genetic origin) or secondary (due to inflammatory conditions).

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 nicotinic acid. As a result, tryptophan is no longer a source of nicotinic acid and deficiency of the vitamin can develop. 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.[1][2][3][4]

Acquired and inherited enzyme deficiencies

Downregulation of kynurenine 3-monooxygenase (KMO) can be caused by genetic polymorphisms, cytokines, or both.[5][6] KMO deficiency leads to an accumulation of kynurenine and to a shift within the tryptophan metabolic pathway towards kynurenic acid and anthranilic acid.[7][8][9][10][11][12]

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.[7] For example, kynurenine 3-monooxygenase deficiency is associated with disorders of the brain (such as schizophrenia and tic disorders) and of the liver.[10][8][9][11][12] 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.[7][6][13][9] 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:[14]

Research

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

Neurodegenerative disease

Scientists are investigating the role of dysregulation of this pathway in aging, neurodegenerative diseases and chronic fatigue syndrome (CFS).[15][16][17]

Kynurenine/tryptophan ratio

Changes in the ratio of kynurenine versus tryptophan are reported for many diseases like arthritis, HIV/AIDS, neuropsychiatric disorders, cancer and inflammations.[18][19][20] The kynurenin/tryptophan is also an indicator for the activity of indoleamine 2,3-dioxygenase (IDO).[21][22]

Methods

Kynurenine metabolites can be quantified using liquid chromatography coupled to mass spectrometry.[23]

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.[24]

References
  1. Cheminal R, Echenne B, Bellet H, Duran M (1996). "Congenital non-progressive encephalopathy and deafness with intermittent episodes of coma and hyperkynureninuria". Journal of Inherited Metabolic Disease. 19 (1): 25–30. doi:10.1007/BF01799345. PMID 8830173.
  2. Komrower GM, Westall R (January 1967). "Hydroxykynureninuria". American Journal of Diseases of Children. 113 (1): 77–80. doi:10.1001/archpedi.1967.02090160127016. PMID 6015911.
  3. Salih MA, Bender DA, McCreanor GM (November 1985). "Lethal familial pellagra-like skin lesion associated with neurologic and developmental impairment and the development of cataracts". Pediatrics. 76 (5): 787–793. PMID 4058988.
  4. Tada K, Yokoyama Y, Nakagawa H, Yoshida T, Arakawa T (October 1967). "Vitamin B6 dependent xanthurenic aciduria". The Tohoku Journal of Experimental Medicine. 93 (2): 115–124. doi:10.1620/tjem.93.115. PMID 5586569.
  5. "Neurobiochemie und Psychopharmakologie" (in German). Klinikums der Universität München. Retrieved 26 May 2014.
  6. Müller N, Myint AM, Schwarz MJ (February 2011). "Inflammatory biomarkers and depression". Neurotoxicity Research. 19 (2): 308–318. doi:10.1007/s12640-010-9210-2. PMID 20658274.
  7. Wonodi I, Stine OC, Sathyasaikumar KV, Roberts RC, Mitchell BD, Hong LE, Kajii Y, Thaker GK, Schwarcz R (July 2011). "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. doi:10.1001/archgenpsychiatry.2011.71. PMC 3855543. PMID 21727251.
  8. Holtze M, Saetre P, Engberg G, Schwieler L, Werge T, Andreassen OA, Hall H, Terenius L, Agartz I, Jönsson EG, Schalling M, Erhardt S (January 2012). "Kynurenine 3-monooxygenase polymorphisms: relevance for kynurenic acid synthesis in patients with schizophrenia and healthy controls". Journal of Psychiatry & Neuroscience. 37 (1): 53–57. doi:10.1503/jpn.100175. PMC 3244499. PMID 21693093.
  9. Campbell BM, Charych E, Lee AW, Möller T (2014). "Kynurenines in CNS disease: regulation by inflammatory cytokines". Frontiers in Neuroscience. 8: 12. doi:10.3389/fnins.2014.00012. PMC 3915289. PMID 24567701.
  10. Hoekstra PJ, Anderson GM, Troost PW, Kallenberg CG, Minderaa RB (June 2007). "Plasma kynurenine and related measures in tic disorder patients". European Child & Adolescent Psychiatry. 16 Suppl 1: 71–77. doi:10.1007/s00787-007-1009-1. PMID 17665285.
  11. Buness A, Roth A, Herrmann A, Schmitz O, Kamp H, Busch K, Suter L (2014). "Identification of metabolites, clinical chemistry markers and transcripts associated with hepatotoxicity". PLOS ONE. 9 (5): e97249. doi:10.1371/journal.pone.0097249. PMC 4023975. PMID 24836604.
  12. Hirata Y, Kawachi T, Sugimura T (October 1967). "Fatty liver induced by injection of L-tryptophan". Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism. 144 (2): 233–241. doi:10.1016/0005-2760(67)90153-1. PMID 4168935.
  13. Maes M, Verkerk R, Bonaccorso S, Ombelet W, Bosmans E, Scharpé S (September 2002). "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. doi:10.1016/s0024-3205(02)01853-2. PMID 12175700.
  14. Stone TW (June 2001). "Kynurenines in the CNS: from endogenous obscurity to therapeutic importance". Progress in Neurobiology. 64 (2): 185–218. doi:10.1016/s0301-0082(00)00032-0. PMID 11240212.
  15. 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):". International Journal of Tryptophan Research. doi:10.4137/IJTR.S11193. PMC 3729338. PMID 23922501.
  16. van der Goot AT, Nollen EA (June 2013). "Tryptophan metabolism: entering the field of aging and age-related pathologies". Trends in Molecular Medicine. 19 (6): 336–344. doi:10.1016/j.molmed.2013.02.007. PMID 23562344.
  17. Schwarcz R, Bruno JP, Muchowski PJ, Wu HQ (July 2012). "Kynurenines in the mammalian brain: when physiology meets pathology". Nature Reviews. Neuroscience. 13 (7): 465–477. doi:10.1038/nrn3257. PMC 3681811. PMID 22678511.
  18. Huengsberg M, Winer JB, Gompels M, Round R, Ross J, Shahmanesh M (April 1998). "Serum kynurenine-to-tryptophan ratio increases with progressive disease in HIV-infected patients". Clinical Chemistry. 44 (4): 858–862. doi:10.1093/clinchem/44.4.858. PMID 9554499.
  19. Schroecksnadel K, Kaser S, Ledochowski M, Neurauter G, Mur E, Herold M, Fuchs D (September 2003). "Increased degradation of tryptophan in blood of patients with rheumatoid arthritis". The Journal of Rheumatology. 30 (9): 1935–1939. PMID 12966593.
  20. Suzuki Y, Suda T, Furuhashi K, Suzuki M, Fujie M, Hahimoto D, Nakamura Y, Inui N, Nakamura H, Chida K (March 2010). "Increased serum kynurenine/tryptophan ratio correlates with disease progression in lung cancer". Lung Cancer (Amsterdam, Netherlands). 67 (3): 361–365. doi:10.1016/j.lungcan.2009.05.001. PMID 19487045.
  21. Widner B, Werner ER, Schennach H, Wachter H, Fuchs D (December 1997). "Simultaneous measurement of serum tryptophan and kynurenine by HPLC". Clinical Chemistry. 43 (12): 2424–2426. doi:10.1093/clinchem/43.12.2424. PMID 9439467.
  22. Fuchs D, Möller AA, Reibnegger G, Stöckle E, Werner ER, Wachter H (1990). "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. PMID 2166783.
  23. 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". Rapid Communications in Mass Spectrometry. 23 (9): 1371–1379. doi:10.1002/rcm.4013. ISSN 1097-0231.
  24. Park, Hyun Bong; Lam, Yick Chong; Gaffney, Jean P.; Weaver, James C.; Krivoshik, Sara Rose; Hamchand, Randy; Pieribone, Vincent; Gruber, David F.; Crawford, Jason M. (2019). "Bright Green Biofluorescence in Sharks Derives from Bromo-Kynurenine Metabolism". iScience. 19: 1291–1336. doi:10.1016/j.isci.2019.07.019. PMC 6831821. PMID 31402257.
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