Kynurenine pathway

The kynurenine pathway is a metabolic pathway leading to the production of nicotinamide adenine dinucleotide (NAD+) from the degradation of the essential amino acid tryptophan. 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][5]

Acquired and inherited enzyme deficiencies

Downregulation of kynurenine-3-monooxygenase (KMO) can be caused by genetic polymorphisms, cytokines, or both.[6][7] KMO deficiency leads to an accumulation of kynurenine and to a shift within the tryptophan metabolic pathway towards kynurenic acid and anthranilic acid.[8][9][10][11][12][13]

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.[14] For example, Kynurenine 3-monooxygenase deficiency is associated with disorders of the brain (e.g. schizophrenia, tic disorders) and of the liver.[15] [16][17][18][19][20] 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 Indolamine-2,3-Dioxygenase (IDO) and Tryptophan-2,3-Dioxygenase (TDO) and/or due to genetic polymorphisms afflicting the particular genes.[21][22][23][24] Dysfunctional states of distinct steps of the kynurenine pathway (e.g. kynurenine, kynurenic acid, quinolinic acid, anthranilic acid, 3 -Hydroxykynurenine) have been described for a number of disorders, e.g.:[25][26]

Research

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

Aging

Scientists are investigating the role of dysregulation of this pathway in aging and neurodegenerative diseases.[27]

Kynurenine/Tryptophan ratio

Changes in the ratio of kynurenine versus tryptophan are reported for many diseases like e.g. arthritis, HIV/AIDS, neuropsychiatric disorders, cancer and inflammations.[28][29][30] The ratio of Kynurenin/Tryptophan is also an indicator for the activity of Indolamine-2,3-Dioxygenase (IDO).[31][32]

References

  1. ↑ Cheminal, R., Echenne, B., Bellet, H., Duran, M. Congenital non-progressive encephalopathy and deafness with intermittent episodes of coma and hyperkynureninuria. J. Inherit. Metab. Dis. 19: 25–30, 1996.
  2. ↑ Komrower, G. M., Westall, R. Hydroxykynureninuria. Am. J. Dis. Child. 113: 77–80, 1967.
  3. ↑ Komrower, G. M., Wilson, V., Clamp, J. R., Westall, R. G. Hydroxykynureninuria: a case of abnormal tryptophane metabolism probably due to a deficiency of kynureninase. Arch. Dis. Child. 39: 250–256, 1964.
  4. ↑ Salih, M. A. M., Bender, D. A., McCreanor, G. M. Lethal familial pellagra-like skin lesion associated with neurologic and developmental impairment and the development of cataracts. Pediatrics 76: 787–793, 1985.
  5. ↑ Tada, K., Yokoyama, Y., Nakagawa, H., Yoshida, T., Arakawa, T. Vitamin B6 dependent xanthurenic aciduria. Tohoku J. Exp. Med. 93: 115–124, 1967.
  6. ↑ http://www.klinikum.uni-muenchen.de/Institut-fuer-Laboratoriumsmedizin/de/forschung/neurobiochemie/index.html (Website in German). Retrieved 26 May 2014
  7. ↑ Müller N, Myint AM, Schwarz MJ: (2010) Inflammatory Biomarkers and Depression. Neurotox Res. 19: 308-318.
  8. ↑ Ikwunga Wonodi, MD; O. Colin Stine, PhD; Korrapati V. Sathyasaikumar etal.: Downregulated Kynurenine 3-Monooxygenase Gene Expression and Enzyme Activity in Schizophrenia and Genetic Association With Schizophrenia Endophenotypes. Arch Gen Psychiatry. 2011;68(7):665-674
  9. ↑ Maria Holtze, MSc, Peter Saetre, PhD, Göran Engberg, et al.: Kynurenine 3-monooxygenase polymorphisms: relevance for kynurenic acid synthesis in patients with schizophrenia and healthy controls. J Psychiatry Neurosci. Jan 2012; 37(1): 53–57.
  10. ↑ Brian M.Campbell, Erik Charych,Anna W. Lee, Thomas Möller: Kynurenines in CNS disease: regulation byinflammatory cytokines. Frontiers in Neuroscience. Neuroendocrine Science February 2014, Volume 8, Article 12.
  11. ↑ Hoekstra PJ, Anderson GM, Troost PW: Plasma kynurenine and related measures in tic disorder patients. Eur Child Adolesc Psychiatry. 2007 Jun;16 Suppl 1:71-7.
  12. ↑ Buness A, Roth A, Herrmann A, Schmitz O, Kamp H, et al. (2014) Identification of Metabolites, Clinical Chemistry Markers and Transcripts Associated with Hepatotoxicity. PLoS ONE 9(5): e97249. doi:10.1371/journal.pone.0097249
  13. ↑ Hirata Yukiko, Kawachi Takashi, Sugimura Takashi: Fatty liver induced by injection of L-tryptophan. Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism. Volume 144, Issue 2, 2 October 1967, Pages 233–241.
  14. ↑ Ikwunga Wonodi, MD; O. Colin Stine, PhD; Korrapati V. Sathyasaikumar etal.: Downregulated Kynurenine 3-Monooxygenase Gene Expression and Enzyme Activity in Schizophrenia and Genetic Association With Schizophrenia Endophenotypes. Arch Gen Psychiatry. 2011;68(7):665-674
  15. ↑ Hoekstra PJ, Anderson GM, Troost PW: Plasma kynurenine and related measures in tic disorder patients. Eur Child Adolesc Psychiatry. 2007 Jun;16 Suppl 1:71–77.
  16. ↑ Maria Holtze, MSc, Peter Saetre, PhD, Göran Engberg, et al.: Kynurenine 3-monooxygenase polymorphisms: relevance for kynurenic acid synthesis in patients with schizophrenia and healthy controls. J Psychiatry Neurosci. Jan 2012; 37(1): 53–57.
  17. ↑ Brian M.Campbell, Erik Charych,Anna W. Lee, Thomas Möller: Kynurenines in CNS disease: regulation byinflammatory cytokines. Frontiers in Neuroscience. Neuroendocrine Science February 2014, Volume 8, Article 12.
  18. ↑ Hoekstra PJ, Anderson GM, Troost PW: Plasma kynurenine and related measures in tic disorder patients. Eur Child Adolesc Psychiatry. 2007 Jun;16 Suppl 1:71-7.
  19. ↑ Buness A, Roth A, Herrmann A, Schmitz O, Kamp H, et al. (2014) Identification of Metabolites, Clinical Chemistry Markers and Transcripts Associated with Hepatotoxicity. PLoS ONE 9(5): e97249. doi:10.1371/journal.pone.0097249
  20. ↑ Hirata Yukiko, Kawachi Takashi, Sugimura Takashi: Fatty liver induced by injection of L-tryptophan. Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism. Volume 144, Issue 2, 2 October 1967, Pages 233–241.
  21. ↑ Ikwunga Wonodi, MD; O. Colin Stine, PhD; Korrapati V. Sathyasaikumar etal.: Downregulated Kynurenine 3-Monooxygenase Gene Expression and Enzyme Activity in Schizophrenia and Genetic Association With Schizophrenia Endophenotypes. Arch Gen Psychiatry. 2011;68(7):665–674.
  22. ↑ Müller N, Myint AM, Schwarz MJ: (2010) Inflammatory Biomarkers and Depression. Neurotox Res. 19: 308–318.
  23. ↑ Michael Maes, Robert Verkerkc, Stephania Bonaccorso: 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, Volume 71, Issue 16, 6. September 2002, Pages 1837–1848.
  24. ↑ Brian M.Campbell, Erik Charych,Anna W. Lee, Thomas Möller: Kynurenines in CNS disease: regulation byinflammatory cytokines. Frontiers in Neuroscience. Neuroendocrine Science February 2014, Volume 8, Article 12.
  25. ↑ Trevor W. Stone: Kynurenines in the CNS: from endogenous obscurity to therapeutic importance. Progress in Neurobiology 64 (2001) 185–218
  26. ↑ Abdollahi, Mostafa: Case Study Oshtoran Syndrome Retrieved June 3, 2016
  27. ↑ van der Goot AT, Nollen EA (2013). "Tryptophan metabolism: entering the field of aging and age-related pathologies". Trends Mol Med. 19 (6): 336–44. doi:10.1016/j.molmed.2013.02.007. PMID 23562344.
  28. ↑ Mia Huengsberg, John B. Winer, Mark Gompels: Serum kynurenine-to-tryptophan ratio increases with progressive disease in HIV-infected patients. Clinical Chemistry April 1998 vol. 44 no. 4 858–862.
  29. ↑ K. Schroecksnadel, S. Kaser, G. Neurauter, et al.: Increased Degradation of Tryptophan in Blood of Patients with Rheumatoid Arthritis. The Journal of Rheumatology 2003; 30:9.
  30. ↑ Yuzo Suzuki, Takafumi Suda, Kazuki Furuhashi, et al.: Increased serum kynurenine/tryptophan ratio correlates with disease progression in lung cancer. Lung Cancer Volume 67, Issue 3 , S. 361–365, March 2010
  31. ↑ Bernhard Widner, Ernst R. Werner, Harald Schennach, et al.: Simultaneous Measurement of Serum Tryptophan and Kynurenine by HPLC. Clinical Chemistry December 1997 vol. 43 no. 12, 2424–2426.
  32. ↑ Fuchs, Dietmar; Möller, Arnulf A.; Reibnegger, Gilbert; et. al.: 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: September 1990.
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