This enzyme participates in the degradation of glutamate and 4-aminobutyrate. It is similar to EC 1.2.1.79 [succinate-semialdehyde dehydrogenase (NADP+)], and EC 1.2.1.16 [succinate-semialdehyde dehydrogenase (NAD(P)+)], but is specific for NAD+.
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SYSTEMATIC NAME
IUBMB Comments
succinate-semialdehyde:NAD+ oxidoreductase
This enzyme participates in the degradation of glutamate and 4-aminobutyrate. It is similar to EC 1.2.1.79 [succinate-semialdehyde dehydrogenase (NADP+)], and EC 1.2.1.16 [succinate-semialdehyde dehydrogenase (NAD(P)+)], but is specific for NAD+.
SSADH is widely expressed throughout most brain regions, although a particularly strong expression is observed in the primary and secondary motor cortex, the amygdala, and the basal ganglia
succinic semialdehyde dehydrogenase (SSADH) deficiency (SSADHD) is a heritable disorder of gamma-aminobutyric acid (GABA) metabolism associating with elevated GABA and gamma-hydroxybutyrate (GHB). The heterogeneous phenotype ranges from mild to severe, including developmental delay, movement abnormalities, neuropsychiatric morbidity, and seizures murine succinic semialdehyde dehydrogenase deficiency (SSADHD) manifests with high concentrations of gamma-aminobutyric acid (GABA) and gamma-hydroxybutyrate (GHB) and low glutamine in the brain
at approximately postnatal day 16-22 SSADH-deficient mice display ataxia and loss of motor control, and develop generalized seizures leading to rapid death by the fourth week of life. D-2-hydroxyglutarate and 4,5-dihydroxyhexanoic acid are elevated in SSADH-deficient mice. SSADH-deficient mice demonstrate a 20% reduction in the ethanolamine glycerophospholipid content as compared to wild type littermates while other brain phospholipids (choline glycerophospholipid, phosphatidylserine and phosphatidylinositol) are not affected
under normal physiological conditions, SSADH works in tandem with GABA transaminase to convert the carbon backbone of gamma-aminobutyric acid to succinate, the latter a source of energy within the tricarboxylic acid cycle. SSADH, in brain, is the major aldehyde dehydrogenase responsible for 4-hydroxy-trans-2-nonenal disposition, but only a minor contributor to its metabolism in liver
aldh5a1-/- (SSADHD) mice and their genetic controls (aldh5a1+/+) are exposed to either a 4% (w/w) glutamine-containing diet or a glutamine-free diet from conception until postnatal day 30. The test diet increases hepatic glutamate in both genotypes, decreases glutamine in aldh5a1+/+ but not in aldh5a1-/-, but has no effect on GABA. Dried bloodspot analyses show significantly elevated GABA in mutants (approximately 800% above controls) and decreased glutamate (approximately 25%), but no glutamine difference with controls. Glutamine supplementation does not impact blood GABA but significantly increased glutamine and glutamate in both genotypes indicating systemic exposure to dietary glutamine. Ataxia and pronounced hyperactivity are observed in aldh5a1-/- mice but remain unchanged by the diet intervention. Glutamine supplementation improves peripheral but not central glutamine deficiency in experimental SSADHD. Murine SSADHD presents with dramatic changes in amino acid levels including a significant elevation in brain GABA, one of the major inhibitory neurotransmitters, a moderate increase in excitatory neurotransmitter glutamate, and a very significant decrease in brain glutamine, the metabolic precursor of glutamate. Phenotype, overview
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OXIDATION STABILITY
ORGANISM
UNIPROT
LITERATURE
when reduced wild type SSADH is treated with hydrogen peroxide, the protein is almost completely inactivated and recovers its activity when the environment is switched back to a reduced state
SSADH (Aldh5a1) deficiency is a rare autosomal recessive disease. Hippocampal and cortical dysfunction in Aldh5a1-/- brain, but no evidence that accumulating key metabolites of SSADH deficiency directly induce impairment of energy metabolism
Enzymatic and metabolic evidence for a region specific mitochondrial dysfunction in brains of murine succinic semialdehyde dehydrogenase deficiency (Aldh5a1-/- mice)
Neurotransmitter alterations in embryonic succinate semialdehyde dehydrogenase (SSADH) deficiency suggest a heightened excitatory state during development
Circadian distribution of generalized tonic-clonic seizures associated with murine succinic semialdehyde dehydrogenase deficiency, a disorder of GABA metabolism
Succinic semialdehyde dehydrogenase from the parasitic cattle tick Rhipicephalus microplus: gene identification, biochemical characterization and comparison with the mouse ortholog