Cloned (Comment) | Organism |
---|---|
gene ALDH5A1 gene, located in the 6p22.3 region, genotyping, recombinant epression of wild-type and mutant enzymes in HEK-293 cells, quantitative RT-PCR expression analysis | Homo sapiens |
Protein Variants | Comment | Organism |
---|---|---|
A237S/T423S | naturally occuring mutation, the mutant shows about 70% reduced activity compared to wild-type | Homo sapiens |
G176R | naturally occuring mutation, the p.G176R change, alone or in combination with p.H180Y, causes the abolishment of enzyme activity. Amino acid replacements G176R and H180Y are located in the same beta-segment that is at the interface between the monomers. The introduction of the positive charges of arginines, in presence of the bulky sidechains of tyrosines, could inhibit the correct tetramer assembly, thus causing instability | Homo sapiens |
G176R/H180Y | naturally occuring mutation, the p.G176R change, alone or in combination with p.H180Y, causes the abolishment of enzyme activity | Homo sapiens |
G176R/H180Y/A237S/T423S | naturally occuring mutation, an Italian SSADHD patient shows heterozygosity for four missense mutations: c.526G>A (p.G176R), c.538C>T (p.H180Y), c.709G>T (p.A237S) and c.1267A>T (p.T423S). The p.G176R change, alone or in combination with p.H180Y, causes the abolishment of enzyme activity. Clinical and cognitive evaluations, phenotype, overview | Homo sapiens |
additional information | lowest stability for the tetramer constituted by G176R/H180Y monomers and the highest stability for that constituted by A237S/T423S monomers. The combination of the two double mutant alleles produces a synergic negative effect on SSADH enzyme activity and stability, thus resulting in SSADHD phenotype | Homo sapiens |
Localization | Comment | Organism | GeneOntology No. | Textmining |
---|---|---|---|---|
mitochondrion | - |
Homo sapiens | 5739 | - |
Natural Substrates | Organism | Comment (Nat. Sub.) | Natural Products | Comment (Nat. Pro.) | Rev. | Reac. |
---|---|---|---|---|---|---|
succinate semialdehyde + NAD+ + H2O | Homo sapiens | - |
succinate + NADH + 2 H+ | - |
? |
Organism | UniProt | Comment | Textmining |
---|---|---|---|
Homo sapiens | P51649 | - |
- |
Source Tissue | Comment | Organism | Textmining |
---|---|---|---|
brain | brain stem, cerebellar dentate nuclei, globus pallidus, and subthalamic nuclei | Homo sapiens | - |
Substrates | Comment Substrates | Organism | Products | Comment (Products) | Rev. | Reac. |
---|---|---|---|---|---|---|
succinate semialdehyde + NAD+ + H2O | - |
Homo sapiens | succinate + NADH + 2 H+ | - |
? |
Subunits | Comment | Organism |
---|---|---|
homotetramer | - |
Homo sapiens |
More | each SSADH monomer comprises an N-terminal domain (for NAD+ binding), a catalytic domain (for SSA recognition), and an oligomerization beta-structured domain. In a dynamic catalytic loop, Cys340 and Glu306 are involved in SSA binding and oxidation. Analysis of the tetramer stability by in silico protein modelling analysis | Homo sapiens |
Synonyms | Comment | Organism |
---|---|---|
ALDH5A1 | - |
Homo sapiens |
succinic semialdehyde dehydrogenase | - |
Homo sapiens |
Cofactor | Comment | Organism | Structure |
---|---|---|---|
NAD+ | - |
Homo sapiens |
General Information | Comment | Organism |
---|---|---|
malfunction | succinic semialdehyde dehydrogenase deficiency (SSADHD) is a rare autosomal-recessively inherited metabolic disorder of GABA catabolism that results in the accumulation of 4-hydroxybutyrate (GHB) in tissues, cerebrospinal fluid, blood and urine. The clinical phenotype of SSADHD is highly variable, ranging from mild intellectual and developmental disabilities to severe neurological defects such as seizures, hypotonia, ataxia and behavioural problems, especially in older patients. The most common abnormalities on cerebral MRI consist of increased T2-weighted signal involving the cerebellar dentate nuclei, globus pallidus, and subthalamic nuclei symmetrically, as well as the subcortical white matter and brainstem. In SSADHD, the final step of the GABA degradation pathway shifts towards a massive reduction of SSA to gamma-hydroxybutyrate (GHB) through either specific or non-specific oxidoreductase reactions. The abnormal accumulation of GHB, eventually excreted in urine, is the pathognomonic disease marker | Homo sapiens |
physiological function | enzyme SSADH is a NAD+-dependent mitochondrial homotetrameric allosteric enzyme and works with gamma-aminobutyric acid (GABA) transaminase to convert GABA to succinic semialdehyde (SSA) which is, in turn, oxidized by SSADH to succinic acid. Besides its established role in GABA catabolism, SSADH is reported to contribute to the antioxidative mitochondrial defence by oxidation of 4-hydroxynonenal, a degradation end product of peroxidated lipids | Homo sapiens |