Neurochemical Research

, Volume 5, Issue 3, pp 223–239 | Cite as

l-Kynurenine Its synthesis and possible regulatory function in brain

  • E. Martin Gál
  • Arnold D. Sherman
Overview

Abstract

One pathway by which tryptophan is metabolized in the brain as well as in the periphery is through cleavage of the indole ring to formylkynurenine and then kynurenine. Indoleamine-2,3-dioxygenase, the enzyme that catalyzes this clavage, and kynurenine are distributed all across the different anatomic regions of brain. Approximately 40% of the kynurenine in brain is synthesized there, the remainder having come from plasma. Tryptophan loading, which has been used both experimentally and therapeutically as a means of increasing tryptophan conversion to serotonin, also increases kynurenine formation in the brain and in the periphery. Because of the formation of kynurenine, which competes for cerebral transport and cellular uptake ofl-tryptophan, and because of substrate inhibition on tryptophan hydroxylase, excessively high doses of tryptophan may actually decrease the production of cerebral serotonin and 5-hydroxyindoleacetic acid.

Keywords

Serotonin Tryptophan Indole Regulatory Function Cellular Uptake 

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References

  1. 1.
    Kotake, Y. 1931. Uber den Mechanismus der Kynurensaurebildung in Organismus. Hoppe-Seyler's Zeitsch. Physiol Chem. 195:158–166.Google Scholar
  2. 2.
    Greenberg, D. M. 1969. Carbon catabolism of amino acids. Pages 153–178in Greenberg, D. M. (ed.), Metabolic Pathway, Vol. 3, Academic Press, New York.Google Scholar
  3. 3.
    Wurtman, R. J., andFernstrom, J. D. 1972,l-Tryptophan,l-tyrosine, and the control of brain monamine biosynthesis. Pages 143–193,in Schneider, S. H. (ed.), Perspectives in Neuropharmacology, Oxford Press, New York.Google Scholar
  4. 4.
    Coppen, A. J. 1972. Indolamines and affective disorders. J. Psychiatr. Res. 9:163–175.Google Scholar
  5. 5.
    Moir, A. T. B., andEccelston, D. 1968. The effects of precursor loading in the cerebral metabolism of 5-hydroxyindoles. J. Neurochem. 15:1093–1108.Google Scholar
  6. 6.
    Young, S. N., andSourkes, T. L. 1977. Tryptophan in the central nervous system: Regulation and Significance. Pages 133–191,in Agranoff, B. W., and Aprison, M. H. (eds.), Advances in Neurochemistry, Vol. 2, Plenum Press, New York.Google Scholar
  7. 7.
    Gál, E. M., Armstrong, J. C., andGinsberg, B. 1966. The nature of in vitro hydroxylation ofl-tryptophan by brain tissue. J. Neurochem. 13:643–654.Google Scholar
  8. 8.
    Gál, E. M. 1974. Cerebral tryptophan-2,3-dioxygenase (pyrrolase) and its induction in rat brain. J. Neurochem. 22:861–863.Google Scholar
  9. 9.
    Higuchi, K., andHayaishi, O. 1967. Enzyme formation ofd-kynurenine fromd-tryptophan. Arch. Biochem. Biophys. 120:397–403.Google Scholar
  10. 10.
    Hirata, F., andHayaishi, O. 1972. New degradative routes of 5-hydroxytryptophan and serotonin by intestinal tryptophan 2,3-dioxygenase. Biochem. Biophys. Res. Commun. 47:112–119.Google Scholar
  11. 11.
    Tsuda, H., Noguchi, T., andKido, R. 1972. 5-Hydroxytryptophan pyrrolase in brain. J. Neurochem. 19:887–889.Google Scholar
  12. 12.
    Gál, E. M., Young, R. B., andSherman, A. D. 1978. Tryptophan loading: Consequent effects on the synthesis of kynurenine and 5-hydroxyindoles in rat brain. J. Neurochem. 31:237–244.Google Scholar
  13. 13.
    Fujiwara, M., Shibata, M., Watanabe, Y., Nukiwa, T., Hirata, F., Mizuno, N., andHayaishi, O. 1978. Indoleamine 2,3-dioxygenase: Formation ofl-kynurenine froml-tryptophan in cultured rabbit pineal gland. J. Biol. Chem. 253:6081–6085.Google Scholar
  14. 14.
    Gál, E. M., andSherman, A. D. 1978. Synthesis and metabolism ofl-kynurenine in rat brain. J. Neurochem. 30:607–613.Google Scholar
  15. 15.
    Joseph, M. H. 1977. The determination of kynurenine by gas-liquid chromatography; evidence for its presence in rat brain. Br. J. Pharmocol. 59:525P.Google Scholar
  16. 16.
    Joseph, M. H., Young, S. N., andCurzon, G. 1976. The metabolism of a tryptophan load in rat brain and liver. The influence of hydrocortisone and allopurinol. Biochem. Pharmacol. 25:2599–2604.Google Scholar
  17. 17.
    Wurtman, R. J., andFernstrom, J. D. 1976. Commentary—Control of brain neurotransmitter synthesis by precursor availability and nutritional state. Biochem. Pharmacol. 25:1691–1696.Google Scholar
  18. 18.
    Curzon, G., andGreen, A. R. 1971. Regional and subcellular changes in the concentration of 5-hydroxytryptamine and 5-hydroxyindole acetic acid in the rat brain caused by hydrocortisone,Dl-α-methyltryptophan,l-kynurenine and immobilization. Br. J. Pharmacol. 43:39–52.Google Scholar
  19. 19.
    Kielly, M., andSourkes, T. L. 1972. Transport ofl-tryptophan into slices of rat cerebral cortex. J. Neurochem. 19:2863–2872.Google Scholar
  20. 20.
    Freidman, P. A., Kappelman, A. H., andKaufman, S. 1972. Partial purification and characterization of tryptophan hydroxylase from rabbit hindbrain. J. Biol. Chem. 247:4165–4173.Google Scholar
  21. 21.
    Gál, E. M. 1975. Relevance of cerebral tryptophan metabolism. Pavlovian J. Biol. Sci. 10:145–160.Google Scholar
  22. 22.
    Shields, P. J., andEccleston, D. 1973. Evidence for the synthesis and storage of 5-hydroxytryptamine in two separate pools in the brain. J. Neurochem. 20:881–888.Google Scholar
  23. 23.
    Hirata, F., Hayaishi, O., Tokuyama, T., andSenoh, S. 1974. In vitro and in vivo formation of two new metabolites of melatonin. J. Biol. Chem. 249:1311–1313.Google Scholar
  24. 24.
    Green, A. R., andCurzon, G. 1970. The effect of tryptophan metabolites in brain 5-hydroxytryptamine metabolism. Biochem. Pharmacol. 19:2061–2068.Google Scholar
  25. 25.
    Makino, K., Joh, Y., andHasegawa F. 1961/62. The detection of mausamine in the brain of mouse. Biochem. Biophys. Res. Commun. 6:432–437.Google Scholar
  26. 26.
    Makino, K., Joh, Y., Hasegawa, F., andTakahashi, H. 1964. The precursor of 5-hydroxykynuramine. Biochem. Biophys. Acta 86:191–194.Google Scholar
  27. 27.
    Joh, Y., andMakino, K. 1966. 5-Hydroxylation of kynurenine in animals Experientia 22:591–596.Google Scholar
  28. 28.
    Hirata, F., Ohnishi, T., andHayaishi, O. 1977 Indoleamine-2,3-dioxygenase. Characterization and properties of enzyme O2 complex. J. Biol. Chem. 252:4637–4642.Google Scholar
  29. 29.
    Ohnishi, T., Hirata, F., andHayaishi, O. 1977. Indoleamine-2,3-dioxygenase. Potassium superoxide as substrate. J. Biol. Chem. 252:4642–4647.Google Scholar
  30. 30.
    Yamamoto, S., andHayaishi, O. 1967. Tryptophan pyrrolase of rabbit intestine.d-andl-tryptophan cleaving enzyme or enzymes. J. Biol. Chem. 242:5260–5266.Google Scholar
  31. 31.
    Thomas, T. N., Priest, D. G., andZemp, J. W. 1976. Distribution of superoxide dismutase in rat brain. J. Neurochem. 27:309–310.Google Scholar
  32. 32.
    Nishikimi, M. 1975. A function of tetrahydropteridines as co-factors for indoleamine dioxygenase. Biochem. Biophys. Res. Commun. 63:92–98.Google Scholar
  33. 33.
    Bailey, Ch. B., andWagner, C. 1974. Kynurenine formamidase. J. Biol. Chem. 249:4439–4444.Google Scholar
  34. 34.
    Noguchi, T., Haseda, H., Kido, R., andMatsumura, Y. 1970. 5-hydroxykynurenine decarboxylase in rat intestine. J. Biochem. 67:113–121.Google Scholar
  35. 35.
    Okamoto, H., Yamamoto, S., Nozaki, M., andHayaishi, O. 1967. On the submitochondrial localization ofl-kynurenine-3-hydroxylase. Biochem. Biophys. Res. Commun. 26:309–314.Google Scholar
  36. 36.
    Tryptophan metabolism: Biochemistry, pathology and regulation. 1975. Acta vitaminol. et enzymol. XXIX FASC 1–6, 1–345. (Proceedings of the 1st Internat. Symposium, Padua, Italy).Google Scholar
  37. 37.
    Abstracts-ISTRY-77. 1977. Madison, Wisconsin, U.S.A. 1–104.Google Scholar
  38. 38.
    Curzon, G. 1969. A relationship between brain serotonin and adrenocortical serotonin and its possible significance in endogenous depression. Pharmacopsych. Neuropsychopharmacol. 2:234–244.Google Scholar
  39. 39.
    Lapin, I. P. 1972. Interaction of kynurenine and its metabolites with tryptamine, serotonin and its precursors and oxotremonine. Psychopharmacologia 26:237–247.Google Scholar
  40. 40.
    Frieden, E., Westmark, G. W., andSchorr, J. M. 1961. Inhibition of tryptophan pyrrolase by serotonin, epinephrine and tryptophan analogs. Arch. Biochem. Biophys. 92:176–182.Google Scholar
  41. 41.
    Ghosh, D., andForrest, H. S. 1967. Inhibition of tryptophan pyrrolase by some naturally occurring pteridines. Arch. Biochem. Biophys. 120:578–582.Google Scholar
  42. 42.
    Korf, J., Van Praag, H. M., andSebens, J. B. 1972. Serum tryptophan decreased, brain tryptophan increased and brain serotonin synthesis unchanged after probenicid loading. Brain Res. 42:239–242.Google Scholar
  43. 43.
    Prange, A. J., Jr., Wilson, I. C., Lynn, C. W., Alltop, L. B., andStikeleather R. A. 1974.l-Tryptophan in mania. Arch. Gen. Psychiatr. 30:56–62.Google Scholar
  44. 44.
    D'Elia, G., Hanson, L., andRaotma, H. 1978.l-Tryptophan and 5-hydroxytryptophan in treatment of depression (a review). Acta Psychiatr. Scand. 57:239–252.Google Scholar

Copyright information

© Plenum Publishing Corporation 1980

Authors and Affiliations

  • E. Martin Gál
    • 1
  • Arnold D. Sherman
    • 1
  1. 1.Neurochemical Research Laboratories Department of Psychiatry College of MedicineUniversity of IowaIowa City

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