Metabolism - Clinical and Experimental
Volume 55, Issue 3 , Pages 353-358 , March 2006

Metabolism of γ-hydroxybutyrate to d-2-hydroxyglutarate in mammals: further evidence for d-2-hydroxyglutarate transhydrogenase

Preliminary data were presented at the 41st Annual Meeting of the Society for the Study of Inborn Errors of Metabolism, Amsterdam, the Netherlands, 2004.

  • Eduard A. Struys

      Affiliations

    • Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands
    • ,
  • Nanda M. Verhoeven

      Affiliations

    • Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands
    • ,
  • Erwin E.W. Jansen

      Affiliations

    • Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands
    • ,
  • Herman J. ten Brink

      Affiliations

    • Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands
    • ,
  • Maneesh Gupta

      Affiliations

    • Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR, USA
    • ,
  • Terry G. Burlingame

      Affiliations

    • Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR, USA
    • ,
  • Lawrence S. Quang

      Affiliations

    • Division of Pediatric Pharmacology and Critical Care, Rainbow Babies and Children's Hospital, Case Western Reserve University School of Medicine, Cleveland, OH, USA
    • ,
  • Timothy Maher

      Affiliations

    • Department of Pharmaceutical Sciences, Massachusetts College of Pharmacy and Health Sciences, Boston, MA, USA
    • ,
  • Piero Rinaldo

      Affiliations

    • Biochemical Genetics Laboratory, Mayo Clinic College of Medicine, Rochester, MN, USA
    • ,
  • O. Carter Snead

      Affiliations

    • Division of Neurology and The Program in Brain and Behavior, Department of Pediatrics, Faculty of Medicine, Hospital for Sick Children, Toronto, Ontario, Canada
    • ,
  • Amy K. Goodwin

      Affiliations

    • Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA
    • ,
  • Elise M. Weerts

      Affiliations

    • Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA
    • ,
  • P. Rand Brown

      Affiliations

    • Department of Comparative Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
    • ,
  • Tonya C. Murphy

      Affiliations

    • Department of Pharmacology, Physiology and Therapeutics, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND, USA
    • ,
  • Mathew J. Picklo

      Affiliations

    • Department of Pharmacology, Physiology and Therapeutics, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND, USA
    • ,
  • Cornelius Jakobs

      Affiliations

    • Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands
    • ,
  • K. Michael Gibson

      Affiliations

    • Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR, USA
    • Division of Medical Genetics, Departments of Pediatrics and Pathology, University of Pittsburgh School of Medicine and Children's Hospital, Pittsburgh, PA 15213, USA
    • Corresponding Author InformationCorresponding author. Division of Medical Genetics, Departments of Pediatrics and Pathology, University of Pittsburgh School of Medicine, Rangos Research Center, Pittsburgh, PA 15213, USA. Tel.: +1 412 692 7608; fax: +1 412 692 7816.

Received 9 April 2005 ,Accepted 19 September 2005.

References 

  1. Maitre M. The gamma-hydroxybutyrate signaling system in brain: organization and functional implications. Prog Neurobiol. 1997;51:337–361
  2. Wong CG, Gibson KM, Snead OC. From the street to the brain: neurobiology of the recreational drug gamma-hydroxybutyric acid. Trends Pharmacol Sci. 2004;25:29–34
  3. Wong CG, Chan KF, Gibson KM, Snead OC. Gamma-hydroxybutyric acid: neurobiology and toxicology of a recreational drug. Toxicol Rev. 2004;23:3–20
  4. Nicholson KL, Balster RL. GHB: a new and novel drug of abuse. Drug Alcohol Depend. 2001;63:1–22
  5. Brenneisen R, Elsohly MA, Murphy TP, Passarelli J, Russmann S, Salamone SJ, et al. Pharmacokinetics and excretion of gamma-hydroxybutyrate (GHB) in healthy subjects. J Anal Toxicol. 2004;28:625–630
  6. Walkenstein SS, Wiser R, Gudmundsen C, Kimmel H. Metabolism of gamma-hydroxybutyric acid. Biochim Biophys Acta. 1964;86:640–642
  7. Jakobs C, Bojasch M, Monch E, Rating D, Siemes H, Hanefeld F. Urinary excretion of gamma-hydroxybutyric acid in a patient with neurological abnormalities. The probability of a new inborn error of metabolism. Clin Chim Acta. 1981;111:169–178
  8. Kaufman EE, Nelson T, Fales HM, Levin DM. Isolation and characterization of a hydroxyacid-oxoacid transhydrogenase from rat kidney mitochondria. J Biol Chem. 1988;263:16872–16879
  9. Brown GK, Cromby CH, Manning NJ, Pollitt RJ. Urinary organic acids in succinic semialdehyde dehydrogenase deficiency: evidence of α-oxidation of 4-hydroxybutyric acid, interaction of succinic semialdehyde with pyruvate dehydrogenase and possible secondary inhibition of mitochondrial β-oxidation. J Inherit Metab Dis. 1987;10:367–375
  10. Gibson KM, Nyhan WL. Metabolism of [U-14C]-4-hydroxybutyric acid to intermediates of the tricarboxylic acid cycle in extracts of rat liver and kidney mitochondria. Eur J Drug Metab Pharmacokinet. 1989;14:61–70
  11. Vayer P, Mandel P, Maitre M. Conversion of gamma-hydroxybutyrate to gamma-aminobutyrate in vitro. J Neurochem. 1985;45:810–814
  12. Pearl PL, Gibson KM. Clinical aspects of the disorders of GABA metabolism in children. Curr Opin Neurol. 2004;17:107–113
  13. Hogema BM, Gupta M, Senephansiri H, Burlingame TG, Taylor M, Jakobs C, et al. Pharmacologic rescue of lethal seizures in mice deficient in succinate semialdehyde dehydrogenase. Nat Genet. 2001;29:212–216
  14. Gupta M, Hogema BM, Grompe M, Bottiglieri TG, Concas A, Biggio C, et al. Murine succinate semialdehyde dehydrogenase deficiency. Ann Neurol. 2003;54(Suppl 6):S81–S90
  15. Gibson KM, Gupta M, Pearl PL, Tuchman M, Vezina LG, Snead OC, et al. Significant behavioral disturbances in succinic semialdehyde dehydrogenase (SSADH) deficiency (gamma-hydroxybutyric aciduria). Biol Psychiatry. 2003;54:763–768
  16. Gupta M, Polinsky M, Senephansiri H, Snead OC, Jansen EE, Jakobs C, et al. Seizure evolution and amino acid imbalances in murine succinate semialdehyde dehydrogenase (SSADH) deficiency. Neurobiol Dis. 2004;16:556–562
  17. Struys EA, Verhoeven NM, Jansen EEW, ten Brink HJ, Burlingame TG, Gupta M, et al. Gamma-hydroxybutyrate (GHB) metabolism to d-2-hydroxyglutarate (d-2-HG) and 4,5-dihydroxyhexanoate (DHHA): further pathomechanisms in succinate semialdehyde dehydrogenase (SSADH) deficiency. J Inherit Metab Dis. 2004;27(Suppl 1):87
  18. Lukas SE, Griffiths RR, Bradford LD, Brady JV, Daley L. A tethering system for intravenous and intragastric drug administration in the baboon. Pharmacol Biochem Behav. 1982;17:823–829
  19. Goodwin AK, Froestl W, Weerts EM. Involvement of gamma-hydroxybutyrate (GHB) and GABA-B receptors in the acute behavioral effects of GHB in baboons. Psychopharmacol (Berl). 2005;180:342–351
  20. Weerts EM, Goodwin AK, Griffiths RR, Brown PR, Froestl W, Jakobs C, et al. Spontaneous and precipitated withdrawal after chronic intragastric administration of gamma-hydroxybutyrate (GHB) in baboons. Psychopharmacol. 2005;179:678–687
  21. Schuler AM, Gower BA, Matern D, Rinaldo P, Wood PA. Influence of dietary fatty acid chain-length on metabolic tolerance in mouse models of inherited defects of mitochondrial fatty acid beta-oxidation. Molec Genet Metab. 2004;83:322–329
  22. Gibson KM, Aramaki S, Sweetman L, Nyhan WL, DeVivo DC, Hodson AK, et al. Stable isotope dilution analysis of 4-hydroxybutyric acid: an accurate method for quantification in physiological fluids and the prenatal diagnosis of 4-hydroxybutyric aciduria. Biomed Environ Mass Spectrom. 1990;19:89–93
  23. Gibson KM, ten Brink HJ, Schor DS, Kok RM, Bootsma AH, Hoffmann GF, et al. Stable-isotope dilution analysis of d- and l-2-hydroxyglutaric acid: application to the detection and prenatal diagnosis of d- and l-2-hydroxyglutaric aciduria. Pediatr Res. 1993;34:277–280
  24. Murphy TC, Poppe C, Porter JE, Montine TJ, Picklo MJ. 4-Hydroxy-trans-2-nonenoic acid is a gamma-hydroxybutyrate receptor ligand in the cerebral cortex and hippocampus. J Neurochem. 2004;89:1462–1470
  25. Snead OC. Evidence for a G protein–coupled gamma-hydroxybutyric acid receptor. J Neurochem. 2000;75:1986–1996
  26. Martins BM, Dobbek H, Cinkaya I, Buckel W, Messerschmidt A. Crystal structure of 4-hydroxybutyryl-CoA dehydratase: radical catalysis involving a [4Fe-4S] cluster and flavin. Proc Natl Acad Sci U S A. 2004;101:15645–15649
  27. Lee CR. Evidence for the β-oxidation of orally administered 4-hydroxybutyrate in humans. Biochem Med. 1977;17:284–291
  28. Vamecq J, Draye JP, Poupaert JH. Studies on the metabolism of glycolyl-CoA. Biochem Cell Biol. 1990;68:846–851
  29. Gibson KM, Goodman SI, Frerman FE, Glasgow AM. Succinic semialdehyde dehydrogenase deficiency associated with combined 4-hydroxybutyric and dicarboxylic acidurias: potential for clinical misdiagnosis based on urinary organic acid profiling. J Pediatr. 1989;114:607–610
  30. Doherty JD, Roth RH. Metabolism of γ-hydroxy-[1-14C] butyrate by rat brain: relationship to the Krebs cycle and metabolic compartmentation of amino acids. J Neurochem. 1978;30:1305–1309
  31. Snead OC, Furner R, Liu CC. In vivo conversion of gamma-aminobutyric acid and 1,4-butanediol to gamma-hydroxybutyric acid in rat brain. Studies using stable isotopes. Biochem Pharmacol. 1989;38:4375–4380
  32. Roth RH, Giarman NJ. γ-Butyrolactone and γ-hydroxybutyric acid—I. Distribution and metabolism. Biochem Pharmacol. 1966;15:1333–1348
  33. Wagner L, Hoffmann GF, Jakobs C. d-2-Hydroxyglutaric aciduria: evidence of clinical and biochemical heterogeneity. J Inherit Metab Dis. 1988;21:247–250
  34. Struys EA, Salomons GS, Achouri Y, van Schaftingen E, Grosso S, Craigen WJ, et al. Mutations in the d-2-hydroxyglutarate dehydrogenase gene cause d-2-hydroxyglutaric aciduria. Am J Hum Genet. 2005;76:358–360
  35. Kolker S, Pawlak V, Ahlemeyer B, Okun JG, Horster F, Mayatepek E, et al. NMDA receptor activation and respiratory chain complex V inhibition contribute to neurodegeneration in d-2-hydroxyglutaric aciduria. Eur J Neurosci. 2002;16:21–28
  36. Da Silva CG, Bueno AR, Schuck PF, Leipnitz G, Ribeiro CA, Wannmacher CM, et al. d-2-Hydroxyglutaric acid inhibits creatine kinase activity from cardiac and skeletal muscle of young rats. Eur J Clin Invest. 2003;33:840–847
  37. Shaw LMJ, Westerfeld WW. A study of the enzymatic reactions involved in the formation of 5-hydroxy-4-ketohexanoic acid and its isomer, 5-keto-4-hydroxyhexanoic acid. Biochemistry. 1968;7:1333–1338
  38. Schoerken U, Sprenger GA. Thiamin-dependent enzymes as catalysts in chemoenzymatic syntheses. Biochim Biophys Acta. 1998;1385:229–243
  39. Gould GG, Mehta AK, Frazer A, Ticku MK. Quantitative autoradiographic analysis of the new radioligand [(3)H](2E)-(5-hydroxy-5,7,8,9-tetrahydro-6H-benzo[a][7]annulen-6-ylidene) ethanoic acid ([(3)H]NCS-382) at gamma-hydroxybutyric acid (GHB) binding sites in rat brain. Brain Res. 2003;979:51–56
  40. Okun JG, Sauer S, Hoffmann GF, Burlingame TG, Kolker S, Gibson KM. Inhibition of ubiquinone-dependent respiratory chain complexes by 4,5-dihydroxyhexanoic acid in succinate semialdehyde dehydrogenase deficiency. J Inherit Metab Dis. 2003;26(Suppl 2):53
  41. Struys EA, Verhoeven NM, Roos B, Jakobs C. Disease-related metabolites in culture medium of fibroblasts from patients with d-2-hydroxyglutaric aciduria, l-2-hydroxyglutaric aciduria, and combined d/l-2-hydroxyglutaric aciduria. Clin Chem. 2003;49:1133–1138

PII: S0026-0495(05)00366-5

doi: 10.1016/j.metabol.2005.09.009

Metabolism - Clinical and Experimental
Volume 55, Issue 3 , Pages 353-358 , March 2006

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