An overview of gamma-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.
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.
Kaufman
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Laboratory of Cerebral Metabolism, National Institute of Mental Health, United States Public Health Service, Department of Health and Human Services, Bethesda, Maryland 20892.
Nelson
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D000429:Alcohol Oxidoreductases / Q000378:metabolism*; D000818:Animals; D002237:Carbohydrate Dehydrogenases / Q000378:metabolism*; D002244:Carbon / Q000378:metabolism; D002384:Catalysis; D003600:Cytosol / Q000201:enzymology*; D006884:Hydroxybutyrate Dehydrogenase / Q000378:metabolism; D007656:Ketoglutaric Acids / Q000378:metabolism; D007700:Kinetics; D008928:Mitochondria / Q000201:enzymology*; D024101:Mitochondrial Proteins; D010084:Oxidation-Reduction; D012978:Sodium Oxybate / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives / Q000378:metabolism
D007656:Ketoglutaric Acids; D024101:Mitochondrial Proteins; D005680:gamma-Aminobutyric Acid; D002244:Carbon; D012978:Sodium Oxybate; D000429:Alcohol Oxidoreductases; D002237:Carbohydrate Dehydrogenases; C020590:L-glucuronate reductase; D006884:Hydroxybutyrate Dehydrogenase; C019416:4-hydroxybutyrate dehydrogenase; C072878:hydroxyacid-oxoacid transhydrogenase; C009338:succinic semialdehyde