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Information on EC 1.2.1.24 - succinate-semialdehyde dehydrogenase (NAD+) and Organism(s) Homo sapiens and UniProt Accession P51649

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IUBMB Comments
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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Homo sapiens
UNIPROT: P51649
Word Map
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria, Archaea
The taxonomic range for the selected organisms is: Homo sapiens
Synonyms
aldehyde dehydrogenase 5a1, ALDH5A, ALDH5A1, alphaKGSA dehydrogenase, dehydrogenase, succinate semialdehyde, NAD(+)-dependent succinic semialdehyde dehydrogenase, SSADH, SSADH-I, SSADH/ALDH5A1, SSALDH, more
SYNONYM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
aldehyde dehydrogenase 5a1
ALDH5A1
dehydrogenase, succinate semialdehyde
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-
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NAD(+)-dependent succinic semialdehyde dehydrogenase
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-
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SSADH
succinate semialdehyde dehydrogenase
succinate semialdehyde:NAD+ oxidoreductase
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-
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succinic semialdehyde dehydrogenase
succinyl semialdehyde dehydrogenase
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
oxidation
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-
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redox reaction
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-
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reduction
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-
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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+.
CAS REGISTRY NUMBER
COMMENTARY hide
9028-95-9
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SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
4-hydroxy-trans-2-nonenal + NAD+ + H2O
4-hydroxy-trans-2-nonenoate + NADH + H+
show the reaction diagram
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-
-
-
?
succinate semialdehyde + NAD+ + H2O
succinate + NADH + 2 H+
show the reaction diagram
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-
-
-
?
succinate semialdehyde + NAD+ + H2O
succinate + NADH + H+
show the reaction diagram
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-
-
-
?
acetaldehyde + NAD+ + H2O
acetate + NADH + H+
show the reaction diagram
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2.3% of the activity with succinate semialdehyde
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-
?
glutaric semialdehyde + NAD+ + H2O
glutarate + NADH
show the reaction diagram
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13% of the activity with succinate semialdehyde
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-
?
m-nitrobenzaldehyde + NAD+ + H2O
m-nitrobenzoate + NADH
show the reaction diagram
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4.3% of the activity with succinate semialdehyde
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-
?
p-nitrobenzaldehyde + NAD+ + H2O
p-nitrobenzoate + NADH
show the reaction diagram
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6.5% of the activity with succinate semialdehyde
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-
?
propionaldehyde + NAD+ + H2O
propionate + NADH
show the reaction diagram
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5% of the activity with succinate semialdehyde
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-
?
succinate semialdehyde + NAD+ + H2O
succinate + NADH
show the reaction diagram
succinate semialdehyde + NAD+ + H2O
succinate + NADH + H+
show the reaction diagram
succinate semialdehyde + NADP+ + H2O
succinate + NADPH
show the reaction diagram
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20% of the activity with NAD+
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-
additional information
?
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NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
4-hydroxy-trans-2-nonenal + NAD+ + H2O
4-hydroxy-trans-2-nonenoate + NADH + H+
show the reaction diagram
-
-
-
-
?
succinate semialdehyde + NAD+ + H2O
succinate + NADH + 2 H+
show the reaction diagram
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-
-
-
?
succinate semialdehyde + NAD+ + H2O
succinate + NADH + H+
show the reaction diagram
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-
-
-
?
succinate semialdehyde + NAD+ + H2O
succinate + NADH
show the reaction diagram
Q8N3W7
last enzyme in catabolism of 4-aminobutyric acid. Human SSADH deficiency results in 4-hydroxybutyric aciduria, an autosomal recessive disorder due to an accumulation of 4-aminobutyric acid and 4-hydroxybutyric acid in the CNS
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-
ir
succinate semialdehyde + NAD+ + H2O
succinate + NADH + H+
show the reaction diagram
additional information
?
-
COFACTOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
NADP+
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cofactor
additional information
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human SSADH is active in the reduced state but not in the oxidized state because of disulfide bonding between Cys340 and Cys342 residues. Oxidation induces a large conformational change in the dynamic catalytic loop that consists of 11 residues, including the two cysteines that connect helix alpha8 and strand beta13. As a result, the loop blocks both substrate succinate semialdehyde and cofactor NAD+ binding
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INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
Disulfiram
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0.01 mM
4-hydroxybenzaldehyde
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Disulfiram
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NADH
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NADH is a strong competitive inhibitor with respect to NAD+ and behaves as a non-competitive inhibitor with respect to succinate semialdehyde
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.04
NAD+
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pH and temperature not specified in the publication
0.001
succinate semialdehyde
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pH and temperature not specified in the publication
0.875
acetaldehyde
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0.04 - 125
NAD+
0.58
propionaldehyde
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0.0007 - 6.3
succinate semialdehyde
additional information
additional information
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-
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Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.1 - 0.128
NADH
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
8.6
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assay at
pH RANGE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
8 - 9
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at least 80% of its optimal activity
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
37
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assay at
pI VALUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
7.66
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computer prediction
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
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fetal kidney
Manually annotated by BRENDA team
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mRNA expression
Manually annotated by BRENDA team
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mRNA expression
Manually annotated by BRENDA team
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
malfunction
metabolism
additional information
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human SSADH intrinsic regulatory mechanism, redox-switch modulation, by which large conformational changes are brought about in the catalytic loop through disulfide bonding, enzyme molecular structure, overview
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
Sequence
SSDH_HUMAN
535
0
57215
Swiss-Prot
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
58000
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4 * 58000
191000
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52000
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4 * 52000, gel-filtration
52230
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calculated from sequence, SDS-PAGE
61000
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x * 61000 + x * 63000, SDS-PAGE
63000
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x * 61000 + x * 63000, SDS-PAGE
69000
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2 * 69000, SDS-PAGE
145000
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gel filtration
200000
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gel filtration
232000 - 245000
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non-denaturing PAGE
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
homotetramer
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4 * 58000
?
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x * 61000 + x * 63000, SDS-PAGE
dimer
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2 * 69000, SDS-PAGE
tetramer
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4 * 52000, gel-filtration
additional information
-
human SSADH is active in the reduced state but not in the oxidized state because of disulfide bonding between Cys340 and Cys342 residues. Oxidation induces a large conformational change in the dynamic catalytic loop that consists of 11 residues, including the two cysteines that connect helix alpha8 and strand beta13. As a result, the loop blocks both substrate succinate semialdehyde and cofactor NAD+ binding. Human SSADH activity is regulated by redox-switch modulation, which depends on reversible intra-disulfide binding to the dynamic catalytic loop. Simulations, and protein transformation and configuration modelling to explain the dynamic redox modulation, method optimization, detailed overview
CRYSTALLIZATION/commentary
ORGANISM
UNIPROT
LITERATURE
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
A237S
A273S
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mutant with activity reduction
C223R
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the mutation is associated with gamma-hydroxybutyric aciduria
C223Y
C340A
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inactive mutant that cannot form a disulfide bond even under strong reducing conditions
C342A
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catalytically functional mutant that cannot form a disulfide bond even under strong reducing conditions
G176R
G268E
G409D
G46R
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the mutant shows 87% activity compared to the wild type enzyme
G533R
H180Y
K301E
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naturally occuring homozygous missense mutation c.901A>G, inactive mutant, the mutation leads to semialdehyde dehydrogenase (SSADH) deficiency disorder, phenotype overview. Mutation K301E most likely leads to a loss of NAD+ binding and a predicted decrease in the free energy by 6.67 kcal/mol suggesting a severe destabilization of the protein. Structure-based in silico modeling of the mutant protein
N255S
N335K
P182L
P382L
T233M
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the mutant shows 4% activity compared to the wild type enzyme
A273S
C223R
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missense mutation associated with a dramatic reduction of enzyme activity
H180Y
P182L
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 was switched back to a reduced state
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710898
PURIFICATION/commentary
ORGANISM
UNIPROT
LITERATURE
2 isoenzymes
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Ni-affinity chromatography
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CLONED/commentary
ORGANISM
UNIPROT
LITERATURE
expression of mutant enzymes is expressed after transfection of HEK293 cells
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gene ALDH5A1, screening and genotyping, DNA and amino acid sequence determination and analysis
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transfection of HEK 293 cells
expression in Escherichia coli as His-tag fusion protein
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APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
medicine
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succinic semialdehyde dehydrogenase deficient patients show widespread reduction in benzodiazepine receptor binding on [(11)C]-flumazenil-positron emission tomography
additional information
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in the world population, the c.538C variant of SSADH is proceeding to replace the ancestral c.538T, shared with primates. A significant correlation between the frequencies of the derived alleles in SSADH and microcephalin, which show concerted changes worldwide and, at least in Asian populations, also on a restricted geographical scale
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Ryzlak, M.T.; Pietruszko, R.
Human brain high Km aldehyde dehydrogenase: purification, characterization, and identification as NAD+-dependent succinic semialdehyde dehydrogenase
Arch. Biochem. Biophys.
266
386-396
1988
Homo sapiens
Manually annotated by BRENDA team
Cash, C.D.; Maitre, M.; Ossola, L.; Mandel, P.
Purification and properties of two succinate semialdehyde dehydrogenases from human brain
Biochim. Biophys. Acta
524
26-36
1978
Homo sapiens
Manually annotated by BRENDA team
Chambliss, K.L.; Caudle, D.L.; Hinson, D.D.; Moomaw, C.R.; Slaughter, C.A.; Jakobs, C.; Gibson, K.M.
Molecular cloning of the mature NAD(+)-dependent succinic semialdehyde dehydrogenase from rat and human. cDNA isolation, evolutionary homology, and tissue expression
J. Biol. Chem.
270
461-467
1995
Homo sapiens, Rattus norvegicus
Manually annotated by BRENDA team
Chambliss, K.L.; Zhang, Y.A.; Rossier, E.; Vollmer, B.; Gibson, K.M.
Enzymatic and immunologic identification of succinic semialdehyde dehydrogenase in rat and human neural and nonneural tissues
J. Neurochem.
65
851-855
1995
Homo sapiens, Rattus norvegicus
Manually annotated by BRENDA team
Akaboshi, S.; Hogema, B.M.; Novelletto, A.; Malaspina, P.; Salomons, G.S.; Maropoulos, G.D.; Jakobs, C.; Grompe, M.; Gibson, K.M.
Mutational spectrum of the succinate semialdehyde dehydrogenase (ALDH5A1) gene and functional analysis of 27 novel disease-causing mutations in patients with SSADH deficiency
Hum. Mutat.
22
442-450
2003
Homo sapiens (P51649)
Manually annotated by BRENDA team
Blasi, P.; Boyl, P.P.; Ledda, M.; Novelletto, A.; Gibson, K.M.; Jakobs, C.; Hogema, B.; Akaboshi, S.; Loreni, F.; Malaspina, P.
Structure of human succinic semialdehyde dehydrogenase gene: identification of promoter region and alternatively processed isoforms
Mol. Genet. Metab.
76
348-362
2002
Homo sapiens, Homo sapiens (Q8N3W7)
Manually annotated by BRENDA team
Blasi, P.; Palmerio, F.; Aiello, A.; Rocchi, M.; Malaspina, P.; Novelletto, A.
SSADH variation in primates: intra- and interspecific data on a gene with a potential role in human cognitive functions
J. Mol. Evol.
63
54-68
2006
Gorilla gorilla (Q6A2H1), Homo sapiens, Hylobates lar (Q3MSM3), Pan paniscus, Pan paniscus (Q3MSM4), Pan troglodytes, Pan troglodytes (Q6A2H0), Pongo abelii (Q6A2H2), Pongo pygmaeus pygmaeus (Q6A2H2)
Manually annotated by BRENDA team
Lorenz, S.; Heils, A.; Taylor, K.P.; Gehrmann, A.; Muhle, H.; Gresch, M.; Becker, T.; Tauer, U.; Stephani, U.; Sander, T.
Candidate gene analysis of the succinic semialdehyde dehydrogenase gene (ALDH5A1) in patients with idiopathic generalized epilepsy and photosensitivity
Neurosci. Lett.
397
234-239
2006
Homo sapiens
Manually annotated by BRENDA team
Kang, J.H.; Park, Y.B.; Huh, T.L.; Lee, W.H.; Choi, M.S.; Kwon, O.S.
High-level expression and characterization of the recombinant enzyme, and tissue distribution of human succinic semialdehyde dehydrogenase
Protein Expr. Purif.
44
16-22
2005
Homo sapiens
Manually annotated by BRENDA team
Marchitti, S.A.; Deitrich, R.A.; Vasiliou, V.
Neurotoxicity and metabolism of the catecholamine-derived 3,4-dihydroxyphenylacetaldehyde and 3,4-dihydroxyphenylglycolaldehyde: the role of aldehyde dehydrogenase
Pharmacol. Rev.
59
125-150
2007
Homo sapiens (P51649)
Manually annotated by BRENDA team
Leone, O.; Blasi, P.; Palmerio, F.; Kozlov, A.I.; Malaspina, P.; Novelletto, A.
A human derived SSADH coding variant is replacing the ancestral allele shared with primates
Ann. Hum. Biol.
33
593-603
2007
Homo sapiens, Homo sapiens (P51649)
Manually annotated by BRENDA team
Knerr, I.; Gibson, K.M.; Jakobs, C.; Pearl, P.L.
Neuropsychiatric morbidity in adolescent and adult succinic semialdehyde dehydrogenase deficiency patients
CNS Spectr.
13
598-605
2008
Homo sapiens
Manually annotated by BRENDA team
Malaspina, P.; Picklo, M.J.; Jakobs, C.; Snead, O.C.; Gibson, K.M.
Comparative genomics of aldehyde dehydrogenase 5a1 (succinate semialdehyde dehydrogenase) and accumulation of gamma-hydroxybutyrate associated with its deficiency
Hum. Genomics
3
106-120
2009
Homo sapiens
Manually annotated by BRENDA team
Pearl, P.L.; Gibson, K.M.; Cortez, M.A.; Wu, Y.; Carter Snead, O.; Knerr, I.; Forester, K.; Pettiford, J.M.; Jakobs, C.; Theodore, W.H.
Succinic semialdehyde dehydrogenase deficiency: lessons from mice and men
J. Inherit. Metab. Dis.
32
343-352
2009
Homo sapiens, Mus musculus
Manually annotated by BRENDA team
Kratz, S.V.
Sensory integration intervention: historical concepts, treatment strategies and clinical experiences in three patients with succinic semialdehyde dehydrogenase (SSADH) deficiency
J. Inherit. Metab. Dis.
32
353-360
2009
Homo sapiens
Manually annotated by BRENDA team
Di Rosa, G.; Malaspina, P.; Blasi, P.; Dionisi-Vici, C.; Rizzo, C.; Tortorella, G.; Crutchfield, S.R.; Gibson, K.M.
Visual evoked potentials in succinate semialdehyde dehydrogenase (SSADH) deficiency
J. Inherit. Metab. Dis.
32
S201-S205
2009
Homo sapiens
Manually annotated by BRENDA team
Pearl, P.L.; Gibson, K.M.; Quezado, Z.; Dustin, I.; Taylor, J.; Trzcinski, S.; Schreiber, J.; Forester, K.; Reeves-Tyer, P.; Liew, C.; Shamim, S.; Herscovitch, P.; Carson, R.; Butman, J.; Jakobs, C.; Theodore, W.
Decreased GABA-A binding on FMZ-PET in succinic semialdehyde dehydrogenase deficiency
Neurology
73
423-429
2009
Homo sapiens
Manually annotated by BRENDA team
Langendorf, C.G.; Key, T.L.; Fenalti, G.; Kan, W.T.; Buckle, A.M.; Caradoc-Davies, T.; Tuck, K.L.; Law, R.H.; Whisstock, J.C.
The X-ray crystal structure of Escherichia coli succinic semialdehyde dehydrogenase; structural insights into NADP+/enzyme interactions
PLoS One
5
e9280
2010
Homo sapiens (P51649)
Manually annotated by BRENDA team
Kim, K.J.; Pearl, P.; Jensen, K.; Snead, O.C.; Malaspina, P.; Jakobs, C.; Gibson, K.M.
Succinic semialdehyde dehydrogenase (SSADH): biochemical-molecular-clinical disease mechanisms, redox regulation and functional significance
Antioxid. Redox Signal.
15
691-718
2011
Homo sapiens, Homo sapiens (P51649), Mus musculus
Manually annotated by BRENDA team
Puettmann, L.; Stehr, H.; Garshasbi, M.; Hu, H.; Kahrizi, K.; Lipkowitz, B.; Jamali, P.; Tzschach, A.; Najmabadi, H.; Ropers, H.H.; Musante, L.; Kuss, A.W.
A novel ALDH5A1 mutation is associated with succinic semialdehyde dehydrogenase deficiency and severe intellectual disability in an Iranian family
Am. J. Med. Genet. A
161A
1915-1922
2013
Homo sapiens, Homo sapiens (P51649)
Manually annotated by BRENDA team
Tamazian, G.; Ho Chang, J.; Knyazev, S.; Stepanov, E.; Kim, K.J.; Porozov, Y.
Modeling conformational redox-switch modulation of human succinic semialdehyde dehydrogenase
Proteins
83
2217-2229
2015
Homo sapiens (P51649)
Manually annotated by BRENDA team
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