4-Hydroxybutyric Acid and the Clinical Phenotype of Succinic Semialdehyde Dehydrogenase Deficiency, an Inborn Error of GABA Metabolism

Gibson, Kevin J.; Gf, Hoffmann; Ak, Hodson; Jakobs, C.

doi:10.1055/s-2007-973527

Cited by 127 publications

(98 citation statements)

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“…This rate is similar to the uptake of oleate by the perfused rat liver (37). Note that part of the carbon derived from the catabolism of 4-hydroxy- [3,[4][5][6][7][8][9][10][11][12][13] C 2 ]nonanoate is not converted to acetyl-CoA but is released as shorter carboxylic acids into the perfusate (supplemental Table 2). …”

Section: ⅐Gmentioning

confidence: 53%

“…The mass isotopomer distribution of acetyl-CoA labeled from 4-hydroxy- [3,[4][5][6][7][8][9][10][11][12][13] C 2 ]nonanoate allows us to calculate the contributions of pathways A and B to the production of acetyl-CoA from this substrate. Pathways A and B yield three and four acetyl-CoA, respectively, with one acetyl-CoA being labeled in each pathway.…”

Section: -Phosphoacyl-coas In 4-hydroxyacid Metabolismmentioning

confidence: 99%

“…Experiments with Mice Deficient in Succinic Semialdehyde Dehydrogenase-Mice deficient in succinic semialdehyde dehydrogenase (SSADH Ϫ/Ϫ ) were developed (42) as a model to study the biochemical perturbations found in humans with 4-hydroxybutyric aciduria (12). We assayed the concentrations of 4-P-butyryl-CoA in quick-frozen livers and brains from control, heterozygote, and homozygote mice.…”

Section: Perfusions Of 4-hydroxyacids In 100%mentioning

confidence: 99%

“…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.…”

mentioning

confidence: 99%

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

Zhang

Kombu

Kasumov

et al. 2009

Journal of Biological Chemistry

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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)....

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Section: ⅐Gmentioning

confidence: 53%

Section: -Phosphoacyl-coas In 4-hydroxyacid Metabolismmentioning

confidence: 99%

Section: Perfusions Of 4-hydroxyacids In 100%mentioning

confidence: 99%

mentioning

confidence: 99%

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

Zhang

Kombu

Kasumov

et al. 2009

Journal of Biological Chemistry

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“…8 The degree of impairment resulting from SSADH deficiency is highly variable, from severe neurological impairment to mild developmental delay. 9 This led us to postulate that common sequence variants in the gene with less dramatic effects on the SSADH protein might influence cognitive ability across the broader spectrum of cognitive ability. Our interest was also fueled by the observation that the SSADH gene maps to a region of the genome (6p22), showing both genetic linkage and genetic association to the cognitive phenotype dyslexia.…”

Section: Introductionmentioning

confidence: 99%

A functional polymorphism in the succinate-semialdehyde dehydrogenase (aldehyde dehydrogenase 5 family, member A1) gene is associated with cognitive ability

et al. 2004

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Succinate-semialdehyde dehydrogenase (SSADH) deficiency is a rare cause of learning disability. We have investigated SSADH to assess its contribution to cognitive ability in the general population in both case-control-and family-based analyses. Sequence analysis of SSADH revealed four changes affecting the encoded protein, only one of which had a minor allele whose frequency is even moderately common. We genotyped this functional polymorphism in 197 high-IQ cases, 201 average-IQ controls and 196 parent high-IQ offspring trios. The minor allele was significantly less frequent in high-IQ cases and was significantly less frequently transmitted by parents to high-IQ subjects than chance expectation. A previous study has shown that the minor allele encodes a lower activity enzyme than the major allele. These data suggest that higher SSADH activity is associated with higher intelligence across the general population. The effect is small, with each allele having an effect size translating to about 1.5 IQ points.

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MRS Studies of the Role of Altered Glutamate and GABA Neurotransmitter Metabolism in the Pathophysiology of Epilepsy

Petroff

Spencer

2004

Brain Energetics and Neuronal Activity

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4-Hydroxybutyric Acid and the Clinical Phenotype of Succinic Semialdehyde Dehydrogenase Deficiency, an Inborn Error of GABA Metabolism

Cited by 127 publications

References 10 publications

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

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

A functional polymorphism in the succinate-semialdehyde dehydrogenase (aldehyde dehydrogenase 5 family, member A1) gene is associated with cognitive ability

MRS Studies of the Role of Altered Glutamate and GABA Neurotransmitter Metabolism in the Pathophysiology of Epilepsy

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