Evidence for the Participation of a Cytosolic NADP<sup>+</sup>‐Dependent Oxidoreductase in the Catabolism of γ‐Hydroxybutyrate In Vivo

Kaufman, Elaine E.; Nelson, Thomas

doi:10.1111/j.1471-4159.1987.tb05758.x

Cited by 27 publications

(33 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…As has been found with certain aldehyde reductases (28,29), anticonwlsants such as barbiturates, diphenylhydantoin and valproate are good inhibitors of GHB dehydrogenase (30). In addition, GHB dehydrogenase is inhibited by salicylates (30).…”

mentioning

confidence: 70%

“…One approach used to determine the magnitude of the contribution of GHB dehydrogenase to the metabolism of GHB in vivo was to give rats compounds which inhibit the activity of the enzyme in vitro (30). If GHB dehydrogenase plays a significant role in the metabolism of GHB in a tissue, inhibition of the enzyme in vivo would be expected to result in increased tissue concen.…”

Section: Effects Of Modulators Of Ghb Dehydrogenase Inmentioning

confidence: 99%

“…These results are in agreement with those of Snead (32) who found elevated levels of GHB in brain following administration of sodium valproate. Although each of these compounds also inhibits SSA dehydrogenase (30), which catalyzes the second step in the degradative pathway, it is very unlikely that the degree to which this enzyme would be inhibited is sufficient to elevate the concentration of SSA enough to cause the increase in tissue levels of GHB. The values for the Ki for valproate, for GABA transaminase (29) and for SSA dehydrogenase (29,30) are approximately 10 -2 to 10-3M.…”

Section: Effects Of Modulators Of Ghb Dehydrogenase Inmentioning

confidence: 99%

See 2 more Smart Citations

An overview of ?-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

Kaufman

Nelson

1991

Neurochem Res

Self Cite

View full text Add to dashboard Cite

",/-Hydroxybutyrate (GHB) is a naturally occurring compound present in micromolar concentration in both brain (1,2) and in peripheral tissues (3). This endogenous compound is remarkable in that pharmacological doses of 200-500 mg/kg produce marked behavioral and electroencephalographic changes (4), a profound decrease in cerebral glucose utilization (5), an increase in striatal dopamine levels (6) and a decrease in body temperature (7). High doses of GHB have also been reported to protect neurons (8) and intestinal epithelium (9) against cell death resulting from experimental ischemia. Behavioral changes are not seen with doses of less than 30 mg/ kg, but low doses stimulate the release of prolactin, growth hormone and cortisol (10,11), and doses of 5-10 mg/kg result in an increase in body temperature (12). These actions, and the discovery of high affinity binding sites for GHB in the central nervous system (13), suggest that GHB may have a biological function. Both the origin of endogenous GHB and its catabolism are, therefore, of considerable interest. This review will cover the early work on the degradative pathway for GHB and the discovery of a dual pathway for the initial step in the oxidative catabolism of GHB. The factors which regulate the activity of the

show abstract

mentioning

confidence: 70%

Section: Effects Of Modulators Of Ghb Dehydrogenase Inmentioning

confidence: 99%

Section: Effects Of Modulators Of Ghb Dehydrogenase Inmentioning

confidence: 99%

See 1 more Smart Citation

An overview of ?-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

Kaufman

Nelson

1991

Neurochem Res

Self Cite

View full text Add to dashboard Cite

show abstract

“…The more rapid reduction of levulinate in mitochondria incubated with glutamate and rotenone must be catalyzed by one or more enzymes different from the transhydrogenase of Kaufman (30). The reduction of levulinate by the 4-hydroxybutyrate transhydrogenase would be presumably inhibited by ␣-ketoglutarate derived from glutamate.…”

Section: Interconversion Of Levulinate and 4-hydroxypentanoate-inmentioning

confidence: 99%

Metabolism of Levulinate in Perfused Rat Livers and Live Rats

Harris¹,

Zhang²,

Sadhukhan³

et al. 2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

Calcium levulinate (4-ketopentanoate) is used as an oral and parenteral source of calcium. We hypothesized that levulinate is converted in the liver to 4-hydroxypentanoate, a new drug of abuse, and that this conversion is accelerated by ethanol oxidation. We confirmed these hypotheses in live rats, perfused rat livers, and liver subcellular preparations. Levulinate is reduced to (R)-4-hydroxypentanoate by a cytosolic and a mitochondrial dehydrogenase, which are NADPH-and NADH-dependent, respectively. A mitochondrial dehydrogenase or racemase system also forms (S)-4-hydroxypentanoate. In livers perfused with [ 13 C 5 ]levulinate, there was substantial CoA trapping in levulinyl-CoA, 4-hydroxypentanoyl-CoA, and 4-phosphopentanoyl-CoA. This CoA trapping was increased by ethanol, with a 6-fold increase in the concentration of 4-phosphopentanoylCoA. Levulinate is catabolized by 3 parallel pathways to propionyl-CoA, acetyl-CoA, and lactate. Most intermediates of the 3 pathways were identified by mass isotopomer analysis and metabolomics. The production of 4-hydroxypentanoate from levulinate and its stimulation by ethanol is a potential public health concern.Levulinate (4-ketopentanoate) is a food additive allowed by the Food and Drug Administration. As a calcium salt, it has been used for many years as an oral and intravenous form of calcium administration (1, 2). It is listed in the pharmacopeias of a number of countries (USA, Europe, India, China, Japan, etc). It is also listed in quality control documents of the World Health Organization. The dry salt is sold on the internet as a non-prescription dietary supplement. To the best of our review of the literature, the catabolism of levulinate has not been investigated in mammalian cells. We found one report on the identification of the reduced form of levulinate, 4-hydroxypentanoate, in the urine of children with ␤-ketothiolase deficiency treated with intravenous calcium levulinate (3). We also found an unexplained report of induction of lactic acidosis in premature babies treated with oral calcium levulinate for hypocalcemia (4).Our interest in levulinate arose from our recent study of the metabolism of 4-hydroxyacids, which are products of lipid peroxidation (C 9 , C 6 ) or drugs of abuse (C 4 , C 5 ) (5, 6). We showed that 4-hydroxyacids with 5 or more carbons are metabolized by two new pathways. The first pathway involves the isomerization of 4-hydroxyacyl-CoAs to 3-hydroxyacylCoAs via 4-phosphoacyl-CoAs, a new class of acyl-CoA esters. After isomerization, the 3-hydroxyacyl-CoAs are catabolized via classical ␤-oxidation to acetyl-CoA and, in the case of odd-chain 4-hydroxyacids, to propionyl-CoA. The second pathway involves a sequence of ␤-, ␣-, and ␤-oxidation steps leading to acetyl-CoA, formate and, in the case of even chain 4-hydroxyacids, to propionyl-CoA.The five-carbon 4-hydroxypentanoate, as a racemic mixture, is a new drug of abuse used in lieu of 4-hydroxybutyrate, which is now a controlled substance in the United States (7-11). Based on our previous work...

show abstract

“…In contrast, we identified M4 succinate and other multilabeled citric acid cycle intermediates. These are formed by the oxidation of 4-hydroxybutyrate to succinate via succinate semialdehyde, as shown by the Kaufman group (14,39,40). This is the only known pathway of 4-hydroxybutyrate catabolism.…”

Section: Volume 284 • Number 48 • November 27 2009mentioning

confidence: 99%

Catabolism of 4-Hydroxyacids and 4-Hydroxynonenal via 4-Hydroxy-4-phosphoacyl-CoAs

Zhang

Kombu

Kasumov

et al. 2009

Journal of Biological Chemistry

View full text Add to dashboard Cite

4-Hydroxyacids are products of ubiquitously occurring lipid peroxidation (C 9 , C 6 ) or drugs of abuse (C 4 , C 5 ). We investigated the catabolism of these compounds using a combination of metabolomics and mass isotopomer analysis. Livers were perfused with various concentrations of unlabeled and labeled saturated 4-hydroxyacids (C 4 to C 11 ) or 4-hydroxynonenal. All the compounds tested form a new class of acyl-CoA esters, 4-hydroxy-4-phosphoacyl-CoAs, characterized by liquid chromatography-tandem mass spectrometry, accurate mass spectrometry, and 31 P-NMR. All 4-hydroxyacids with five or more carbons are metabolized by two new pathways. The first and major pathway, which involves 4-hydroxy-4-phosphoacylCoAs, leads in six steps to the isomerization of 4-hydroxyacylCoA to 3-hydroxyacyl-CoAs. The latter are intermediates of physiological ␤-oxidation. The second and minor pathway involves a sequence of ␤-oxidation, ␣-oxidation, and ␤-oxidation steps. In mice deficient in succinic semialdehyde dehydrogenase, high plasma concentrations of 4-hydroxybutyrate result in high concentrations of 4-hydroxy-4-phospho-butyryl-CoA in brain and liver. The high concentration of 4-hydroxy-4-phospho-butyryl-CoA may be related to the cerebral dysfunction of subjects ingesting 4-hydroxybutyrate and to the mental retardation of patients with 4-hydroxybutyric aciduria. Our data illustrate the potential of the combination of metabolomics and mass isotopomer analysis for pathway discovery.4-Hydroxy-n-acids are involved in different areas of mammalian metabolism. Some unsaturated 4-hydroxyacids are derived from 4-hydroxynonenal and 4-hydroxyhexenal, which are products of lipid peroxidation (1). The metabolism of 4-hydroxynonenal has been extensively studied, especially its conjugation with glutathione (2), covalent modification of proteins (3, 4), and conversion to 4-hydroxynonenoate, 4-hydroxynonanoate and 1,4-dihydroxynonene, as well as its role in inflammatory processes (1, 5-11). However, the catabolism of its carbon skeleton has not been unraveled. The four-carbon 4-hydroxybutyrate is a physiological neurotransmitter derived from ␥-aminobutyrate. Humans with inborn disorder of succinic semialdehyde dehydrogenase have high 4-hydroxybutyrate concentrations in body fluids, mental retardation, and seizures (12). 4-Hydroxybutyrate is also a drug of abuse that impairs the capacity to exercise judgment for unknown reasons. 4-Hydroxybutyrate is used for the treatment of narcolepsy (13). Its known metabolism (14, 15) proceeds via oxidation to succinic semialdehyde and then to succinate, an intermediate of the citric acid cycle. The five-carbon 4-hydroxypentanoate is also a drug of abuse (16). The calcium salt of a compound closely related to 4-hydroxypentanoate, levulinate (4-ketopentanoate, 4-ketovalerate), is used as an oral or intravenous source of calcium in humans.We conducted a study on the catabolism of C 4 to C 11 4-hydroxyacids in perfused rat livers using a combination of metabolomics (17,18) and mass isotopomer analysis 2 (19)....

show abstract

Evidence for the Participation of a Cytosolic NADP⁺‐Dependent Oxidoreductase in the Catabolism of γ‐Hydroxybutyrate In Vivo

Cited by 27 publications

References 22 publications

An overview of ?-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

An overview of ?-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

Metabolism of Levulinate in Perfused Rat Livers and Live Rats

Catabolism of 4-Hydroxyacids and 4-Hydroxynonenal via 4-Hydroxy-4-phosphoacyl-CoAs

Contact Info

Product

Resources

About

Evidence for the Participation of a Cytosolic NADP+‐Dependent Oxidoreductase in the Catabolism of γ‐Hydroxybutyrate In Vivo

Cited by 27 publications

References 22 publications

An overview of ?-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

An overview of ?-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

Metabolism of Levulinate in Perfused Rat Livers and Live Rats

Catabolism of 4-Hydroxyacids and 4-Hydroxynonenal via 4-Hydroxy-4-phosphoacyl-CoAs

Contact Info

Product

Resources

About

Evidence for the Participation of a Cytosolic NADP⁺‐Dependent Oxidoreductase in the Catabolism of γ‐Hydroxybutyrate In Vivo