Serotonin pp 197-206 | Cite as

Synthesis and Quantitative Aspects of Dihydrobiopterin Control of Cerebral Serotonin Levels

  • E. Martin Gál
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 133)


Soon after the isolation of 7,8-dihydrobiopterin from rat liver,1 the structure of the naturally occurring cofactor of hydroxylases 5,6,7,8-tetrahydrobiopterin (BH4) was established. Unequivocal proof of the biosynthesis of its precursors quinonoid-D-erythrodihydroneopterin triphosphate and quinonoid-L-erythrodihydrobiopterin from GTP was documented in a series of reports.2,3,4,5 Significant to the understanding of the formation of BH4 was the characterization of an enzyme, quinonoid dihydrobiopterin reductase (DHPR) (EC1.6.99.7) which catalyzes the reduction of quinonoid-L- erythrodihydrobiopterin (q-BH2) in presence of NADH2 or NADPH2.6,7 The coupled oxido-reductive reaction q-BH2+2H++2e⇌BH4+O2+substrate → product +H2O enables the fast shuttle of 2H++2e.


Tyrosine Hydroxylase Dihydrofolate Reductase Pyridine Nucleotide Phenylalanine Hydroxylase Dihydropteridine Reductase 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    S. Kaufman, The structure of phenylalanine hydroxylase cofactor, Proc. Nat. Acad. Sci. U.S.A. 50:1085–1092 (1963).CrossRefGoogle Scholar
  2. 2.
    E. M. Gâl and A. D. Sherman, Biopterin II: Evidence for cerebral synthesis of 7,8-dihydrobiopterin in vivo and in vitro, Neurochem. Res. 1:627–639 (1976).CrossRefGoogle Scholar
  3. 3.
    E. M. Gâl, J. M. Nelson, and A. D. Sherman, Biopterin III: Purification and characterization of enzymes involved in the cerebral synthesis of 7,8-dihydrobiopterin, Neurochem. Res. 3:69–88 (1978).PubMedCrossRefGoogle Scholar
  4. 4.
    E. M. Gâl, F. A. Henn, and A. Sherman, Biopterin IV: Regional and subcellular aspects of L-erythro-7,8-dihydrobiopterin synthesis in brain, Neurochem. Res. 3:493–499 (1978).PubMedCrossRefGoogle Scholar
  5. 5.
    E. M. Gâl and A. D. Sherman, 6-(D-erythro-1’,2’,3’-trihydroxypropyl)-7,8-dihydropterin triphosphate synthetase, Fed. Proc. 38:324 (1979).Google Scholar
  6. 6.
    J. E. Crame, E. S. Hall, and S. Kaufman, The isolation and characterization of dihydropteridine reductase from sheep liver, J.Biol. Chem. 247:6082–6091 (1972).Google Scholar
  7. 7.
    H. Snady and J. M. Musacchio, Quinonoid dihydropterin reductaseII regional and subcellular distribution of rat brain enzyme, Biochem Pharmacol. 27:1947–1953 (1978).PubMedCrossRefGoogle Scholar
  8. 8.
    E. M. Gail, Biosynthesis and function of unconjugated pterins in the mammalian tissues, In “Advances in Neurochemistry vol. 4,” B.W. Agranoff and M. H. Aprison, eds., Plenum Publishing, New York (in press).Google Scholar
  9. 9.
    E. M. Gâl, G. Hanson, and A. D. Sherman, Biopterin I: Profile and quantitation in rat brain, Neurochem. Res. 1:511–523 (1976).CrossRefGoogle Scholar
  10. 10.
    R. A. Levine, D. M. Kuhn, and W. Lovenberg, The regional distribution of hydroxylase cofactor in rat brain, J. Neurochem. 32:1575–1578 (1979).PubMedCrossRefGoogle Scholar
  11. 11.
    E. M. Gál and A. D. Sherman, Rapid isolation and quantitation of biopterin, neopterin, and their guanine ribotide precursor from biological samples, Prep. Biochem. 7(2):155–164 (1978).Google Scholar
  12. 12.
    H.-Ch. Curtius, A. Niederwieser, M. Viscontini, A. Otten, J. Schaub, S. Scheibenreiter, and H. Schmidt, Atypical phenylketonuria due to tetrahydrobiopterin deficiency. Diagnosis and treatment with tetrahydrobiopterin, dihydrobiopterin and sepiapterin, Clin. Chini. Acta. 93:251–262 (1979).CrossRefGoogle Scholar
  13. 13.
    E. M. Gel and A. D. Sherman, Phosphorylation, a factor controlling the synthesis of L-erythrodihydrobiopterin (BH2), Biochem, Biophys. Res. Com. 83:593–598 (1978).CrossRefGoogle Scholar
  14. 14.
    E. M. Gel, M. R. Dawson, D. T. Dudley, and A. D. Sherman, Biopterin VI: Purification and primary amino acid sequence of mammalian D-erythro-7,8-dihydroneopterin triphosphate synthetase, Neurochem. Res. 4:605–626 (1979).CrossRefGoogle Scholar
  15. 15.
    K. Fukushima, W. E. Richter, Jr., and T. Shiota, Partial purification of 6-(D-erythro-1’,2’,3’-trihydroxypropyl)-7, 8-dihydropterin triphosphate synthetase from chicken liver, J. Biol. Chem. 252:5750–5755 (1977).PubMedGoogle Scholar
  16. 16.
    E. M. Ggl, J. A. Bybee, and A. D. Sherman, Biopterin V: De novo synthesis of dihydrobiopterin: evidence for its quinonoid structure and lack of dependence of its reduction to tetrahydrobiopterin on dihydrofolate reductase, J. Neurochem. 32:179–186 (1979).CrossRefGoogle Scholar
  17. 17.
    W. P. Bullard, P. B. Guthrie, V. Russo, and A. J. Mandell, Regional and subcellular distribution and some factors in the regulation of reduced pterins in rat brain, J. Pharmacol. Exp. Ther. 206:4–20 (1978).PubMedGoogle Scholar
  18. 18.
    A. D. Sherman and E. M. Ggl, Lack of dependence of amine or prostaglandin biosynthesis on absolute cerebral level of pteridine cofactor, Life Sciences. 23:1675–1680 (1978).PubMedCrossRefGoogle Scholar
  19. 19.
    E. M. Gel and A. D. Sherman, Synthesis and metabolism of L-kynurenine in rat brain, J. Neurochem. 30:607–613 (1978).CrossRefGoogle Scholar
  20. 20.
    R. Kettler, G. Bartholini, and A. Pletscher, In vivo enhancement of tyrosine hydroxylation in rat striatum by tetrahydrobiopterin, Nature. 249:476–478 (1974).PubMedCrossRefGoogle Scholar
  21. 21.
    E. M. Gel, Tryptophan-5-hydroxylase: function and control, In: “Advances in Biochem. Psychopharmacol., Vol. 11,” E. Costa, G. L. Gessa, and M. Sandler, eds., Raven Press, New York, pp. 1–10 (1974).Google Scholar
  22. 22.
    S. W. Bailey and J. E. Ayling, Separation and properties of the 6-diastereoisomers of L-erythrotetrahydrobiopterin and their reactivities with phenylalanine hydroxylase, J. Biol. Chem. 253:1598–1605 (1978).PubMedGoogle Scholar
  23. 23.
    T. Nagatsu, K. Mizutani, I. Nagatsu, S. Matsuura, and T. Sugimoto, Pteridines as cofactor of inhibitor of tyrosine hydroxylase, Biochem. Pharmacol. 21:1945–1953 (1972).PubMedCrossRefGoogle Scholar
  24. 24.
    T. Lloyd and J. Weisz, Direct inhibition of tyrosine hydroxylase activity by catechol estrogens, J. Biol. Chem. 253:4841–4843 (1978).PubMedGoogle Scholar
  25. 25.
    S. P. Mann and J. I. Gordon, Inhibition of guinea-pig brain tyrosine hydroxylase by catechols and biopterin, J. Neurochem. 33:133–138 (1979).PubMedCrossRefGoogle Scholar
  26. 26.
    B. Jarrott, The cellular localization and physiological role of catechol-O-methyl transferase in the body, In: “Frontiers in Cathecholamine Research,” E. Usdin and S. Snyder, eds., Pergamon Press, New York, pp. 133–138 (1973).Google Scholar
  27. 27.
    B. Zivkovic, A. Guidotti, and E. Costa, Effects of Neuroleptics on striatal tyrosine hydroxylase: Changes in affinity for the pteridine cofactor, Molec. Pharmacol. 10:727–735 (1975).Google Scholar
  28. 28.
    M. Hamon, S. Bourgoin, F. Artaud, and F. Hery, Rat brain stem tryptophan hydroxylase: mechanism of activation by calcium, J. Neurochem. 28:811–818 (1977).PubMedCrossRefGoogle Scholar
  29. 29.
    R. H. Roth and P. M. Salzman, Role of calcium in the depolarization-induced activation of tyrosine hydroxylase, In: “Structure and Function of Monoamine Enzymes,” E. Usdin, N. Weiner, and M. B. H. Youdim, eds., Dekker, New York, pp. 149–168 (1977).Google Scholar
  30. 30.
    S. Kaufman, Metabolism of the phenylalanine hydroxylation cofactor, J. Biol. Chem. 242:3934–3943 (1967).PubMedGoogle Scholar
  31. 31.
    E. M. Gal, M. Poczik, and F. D. Marshall, Hydroxylation of tryptophan to 5-hydroxytryptophan by brain tissue in vivo, Biochem. and Biophys. Res. Com. 12:39–43 (1963).CrossRefGoogle Scholar
  32. 32.
    D. G. Grahame-Smith, Tryptophan hydroxylation in brain, Biochem. and Biophys. Res. Com. 16:586–592 (1964).CrossRefGoogle Scholar
  33. 33.
    E. M. Gal, J. C. Armstrong, and B. Ginsberg, The nature of in vitro hydroxylation of L-tryptophan by brain tissue. J. Neurochem. 13:643–654 (1966).PubMedCrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1981

Authors and Affiliations

  • E. Martin Gál
    • 1
  1. 1.Neurochemical Research Laboratories Department of PsychiatryCollege of Medicine University of IowaIowa CityUSA

Personalised recommendations