Skip to main content
SpringerLink
Log in

An overview of γ-hydroxybutyrate catabolism: The role of the cytosolic NADP+-dependent oxidoreductase EC 1.1.1.19 and of a mitochondrial hydroxyacid-oxoacid transhydrogenase in the initial, rate-limiting step in this pathway

  • Original Articles
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Summary

Two enzymes have been found which catalyze the initial step in the catabolism of GHB. The oxidation of GHB to SSA, catalyzed by both of these enzymes, is coupled to the reduction of an oxoacid. In the case of the mitochondrial transhydrogenase, the coupling is obligatory. Although coupling is not obligatory for the GHB dehydrogenase, the stimulation provided by the coupled reaction, and the nature of the kinetics of the uncoupled reaction, may not only allow the reaction to proceed, but may provide a means of regulating the rate of the reaction under in vivo conditions. Since the oxidation of GHB to SSA is the rate limiting step in the overall catabolic pathway (the rate of conversion of GHB to SSA proceeds at approximately one one thousandth of the rate at which SSA is oxidized to succinate by SSA dehydrogenase (30)), factors which regulate the rate of either or both of these enzymes will, in turn, influence tissue levels of endogenous GHB as well as the duration and magnitude of the physiological effect of a dose of GHB.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

Abbreviations

GHB:

γ-hydroxybutyrate

SSA:

succinic semialdehyde

DTT:

dithiothreitol

References

  1. Roth, R. H., and Giarman, N. J. 1970. Natural occurrence of gamma-hydroxybutyrate in mammalian brain. Biochem. Pharmacol. 19:1087–1093.

    Google Scholar 

  2. Roth, R. H. 1970. Formation and regional distribution of γ-hydroxybutyric acid in mammalian brain. Biochem. Pharmacol. 19:3013–3019.

    Google Scholar 

  3. Nelson, T., Kaufman, E. E., Kline, J. E., and Sokoloff, L. 1981. The extraneural distribution of γ-hydroxybutyrate. J. Neurochem. 37:1345–18.

    Google Scholar 

  4. Winters, W. D., and Spooner, C. F. 1965. A neurophysiological comparison of gamma-hydroxybutyrate with phenobarbital in cats. Electroenceph. Clin. Neurophysiol. 20:83–90.

    Google Scholar 

  5. Wolfson, L. I., Sakurada, O., and Sokoloff, L. 1977. Effects of γ-butyrolactone on local cerebral glucose utilization in the rat. J. Neurochem. 29:777–783.

    Google Scholar 

  6. Roth, R. H., and Suhr, Y. 1970. Mechanism of the gamma-hydroxybutyrate induced increase in brain dopamine and its relationship to ‘sleep’. Biochem. Pharmacol. 19:3001–3012.

    Google Scholar 

  7. Laborit, H., Jouany, J.-M., Gerard, J., and Fabiani, F. 1960. Résumé d'une étude expérimental et clinique sur un substrat métabolique a action centrale inhibitrice le 4-hydroxybutyrate de Na. Presse Medicale 68:1867–1869.

    Google Scholar 

  8. Lavyne, M. H., Hairi, R. J., Tankosic, T., and Babiak, T. 1983. Effect of low dose γ-butyrolactone therapy on forebrain neuronal ischemia in the unrestrained, awake rat. Neurosurg 12:430–434.

    Google Scholar 

  9. Boyd, A. J., Sherman, I. A., Saibil, F. G., and Mamelak, M. 1990. The protective effect of γ-hydroxybutyrate in regional intestinal ischemia in the hamster. Gastroenterology 99:860–862.

    Google Scholar 

  10. Takahara, J., Yunoki, S., Yakushiji, W., Yamauchi, J., Yamane, Y., and Ofuji, T. 1977. Stimulatory effects of γ-hydroxybutyric acid on growth hormone and prolactin release in humans. J. Clin. Endocrinol. Metab. 44:1014–1017.

    Google Scholar 

  11. Yunoki, S. 1982. Studies of gamma-aminobutyric acid (GABA) and its metabolite on the control mechanism of secretion of anterior pituitary hormones. II. Effects of gamma-hydroxybutyric acid (GHB) on secretion of anterior pituitary hormones in human subjects. Okayama Igakkai Zasshi 94:899–913.

    Google Scholar 

  12. Kaufman, E. E., Porrino, L. J., and Nelson, T. 1990. Pyretic action of low doses of γ-hydroxybutyrate in rats. Biochem. Pharmacol. 40:2637–2640.

    Google Scholar 

  13. Maitre, M., and Mandel, P. 1984. Neurobiology. γ-Hydroxybutyrate, a putative neurotransmitter in the central nervous system. Comptes Rendue Acad. Sci. (Paris) 298 Series III:341–345.

    Google Scholar 

  14. Walkenstein, S. S., Wiser, R., Gudmundsen, C., et al. 1964. Metabolism of gamma-hydroxybutyric acid. Biochim. Biophys. Acta 86:640–642.

    Google Scholar 

  15. Möhler, H., Patel, A. J., and Balázs, R. 1976. gamma-Hydroxybutyrate degradation in the brainin vivo: Negligible direct conversion to GABA. J. Neurochem. 27:253–258.

    Google Scholar 

  16. Doherty, J. D., Stout, R. W. and Roth, R. H. 1975. Metabolism of [1-14C]γ-hydroxybutyric acid by rat brain after intraventricular injection. Biochem. Pharmacol. 24:469–474.

    Google Scholar 

  17. Jakobs, C., Bojasch, M., Mönch, E., Rating, D., Siemes, H., and Hanefeld, F. 1981. Urinary excretion of gamma-hydroxybutyric acid in a patient with neurological abnormalities. The probability of a new inborn error of metabolism. Clin. Chim. Acta 111:169–178.

    Google Scholar 

  18. Gibson, K. M., Sweetman, L., Nyhan, W. L., Jakobs, C., Rating, D., Siemes, H. and Hanefeld, F. 1981. Succinic semialdehyde dehydrogenase deficiency: An inborn error of gamma-aminobutyric acid metabolism. Clin. Chim. Acta 133:33–42.

    Google Scholar 

  19. Kaufman, E. E., Nelson, T., Goochee, C. F., and Sokoloff, L. 1979. Purification and characterization of an NADP+-linked alcohol oxido-reductase which catalyzes the interconversion of γ-hydroxybutyrate and succinic semialdehyde. J. Neurochem. 32:699–712.

    Google Scholar 

  20. Kaufman, E. E., Nelson, T., Fales, H. M., and Levin, D. M. 1988. Isolation and characterization of a hydroxyacid-oxoacid transhydrogenase from rat kidney mitochondria. J. Biol. Chem. 263:16872–16879.

    Google Scholar 

  21. York, J. L., Grollman, A. P. and Bublitz, C. 1961. TPN-L-gulonate dehydrogenase. Biochim. Biophys. Acta 47:298–306.

    Google Scholar 

  22. Cromlish, J. A., Yoshimoto, C. K., and Flynn, G. T. 1985. Purification and characterization of four NADPH-dependent aldehyde reductases from pig brain. J. Neurochem. 44:1477–1484.

    Google Scholar 

  23. Kaufman, E. E., and Nelson, T. 1981. Kinetics of coupled γ-hydroxybutyrate oxidation and D-glucuronate reduction by an NADP+-dependent oxidoreductase. J. Biol. Chem. 256:6890–6894.

    Google Scholar 

  24. Segel I. H. 1975. Page 41. Enzyme Kinetics. Wiley Interscience, New York.

    Google Scholar 

  25. Glock, G. E. 1961. Long, C. (ed.), Biochemist's Handbook, Van Nostrand, Princeton.

    Google Scholar 

  26. Kaufman, E. E., Relkin, N., and Nelson, T. 1983. Regulation and properties of an NADP+ oxidoreductase which functions as a γ-hydroxybutyrate dehydrogenase. J. Neurochem. 40:1639–1646.

    Google Scholar 

  27. Vayer, P., Schmitt, M., Bourguignon, J. J., Mandel, P., and Maitre, M. 1985. Evidence for a role of high Km aldehyde reductase in the degradation of endogenous γ-hydroxybutyrate from rat brain. FEBS LETTERS 190:55–60.

    Google Scholar 

  28. Erwin, V. G., and Deitrich, R. A. 1973. Inhibition of bovine brain aldehyde reductase by anticonvulsant compoundsin vitro. Biochem. Pharmacol. 22:2615–2624.

    Google Scholar 

  29. Whittle, S. R., and Turner, A. J. 1978. Effects of the anticonvulsant sodium valproate on γ-aminobutyrate and aldehyde metabolism in ox brain. J. Neurochem. 31:1453–1459.

    Google Scholar 

  30. Kaufman, E. E., and Nelson, T. 1987. Evidence for the participation of a cytosolic NADP+-dependent oxidoreductase in the catabolism of γ-hydroxybutyratein vivo. J. Neurochem. 48:1935–1941.

    Google Scholar 

  31. Kaufman, E. E., Nelson, T., Miller, D., and Stadlan, N. 1988. Oxidation of γ-hydroxybutyrate to succinic semialdehyde by a mitochondrial pyridine nucleotide-independent enzyme. J. Neurochem. 51:1079–1084.

    Google Scholar 

  32. Snead, O. C., III, Bearden, L. J., and Pegram, V. 1980. Effect of acute and chronic anticonvulsant administration on endogenous γ-hydroxybutyrate in rat brain. Neuropharmacology 19:47–52.

    Google Scholar 

  33. Reddy, C. C., Swan, J. S., and Hamilton, G. A. 1981. myo-Inositol oxygenase from hog kidney: 1. Purification and characterization of an enzyme complex containing the oxygenase and D-glucuronate reductase. J. Biol. Chem. 256:8510–8518.

    Google Scholar 

  34. Vickers, M. D. 1969. Gammahydroxybutyric Acid. Int. Anesthesiol. Clin. 7:75–89.

    Google Scholar 

  35. Rumigny, J. F., Cash, C., Mandel, P., Vincendon, G. and Maitre, M. 1981. Evidence that a specific succinic semialdehyde reductase is responsible for γ-hydroxybutyrate synthesis in rat brain tissue slices. FEBS LETTERS 134:96–98.

    Google Scholar 

  36. Mitoma, C., and Neubauer, S. E. 1968. gamma-Hydroxybutyric acid and sleep. Experientia 24:12–13.

    Google Scholar 

  37. DeFeudis, F. V., Delgado, J. M., and Roth, R. H. 1969. Content and release of amino-acids and catecholamines in monkey brain. Nature 223:74–75.

    Google Scholar 

  38. DeFeudis, F. V., and Collier, B. 1970. Amino acids of brain and γ-hydroxybutyrate-induced depression. Archs. Int. Pharmacodyn. Thér. 187:30–36.

    Google Scholar 

  39. Vayer, P., Mandel, P., and Maitre, M. 1985. Conversion of γ-hydroxybutyrate to γ-aminobutyratein vitro. J. Neurochem. 45:810–814.

    Google Scholar 

  40. Baxter, C. F. 1970. The nature of γ-aminobutyric acid. Pages 289–53,in Lajtha, A. (ed.), Handbook of Neurochemistry Volume 3, Plenum, New York.

    Google Scholar 

  41. Kaufman, E. E., Nelson, T., and Fales, H. M. 1990. Isolation and characterization of a mammalian hydroxyacid-oxoacid transhydrogenase. Pages 1059–1069, in, Reddy, C. C., Hamilton, G. A. (eds.), Proceeding of the International Symposium on Biological Oxidation Systems. Volume II, Academic Press, New York.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Health and Human Services, Laboratory of Cerebral Metabolism, National Institute of Mental Health, United States Public Health Service, Building 36, Room 1A-05, 20892, Bethesda, Maryland

    Elaine E. Kaufman & Thomas Nelson

Authors
  1. Elaine E. Kaufman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Thomas Nelson
    View author publications

    You can also search for this author in PubMed Google Scholar

Additional information

Special issue dedicated to Dr. Louis Sokoloff.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kaufman, E.E., Nelson, T. An overview of γ-hydroxybutyrate catabolism: The role of the cytosolic NADP+-dependent oxidoreductase EC 1.1.1.19 and of a mitochondrial hydroxyacid-oxoacid transhydrogenase in the initial, rate-limiting step in this pathway. Neurochem Res 16, 965–974 (1991). https://doi.org/10.1007/BF00965839

Download citation

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00965839

Keywords

Search

Navigation