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At least 19 recordsLinked to original sources
PubMed1975

[Purification of rat brain succinate-semialdehyde dehydrogenase and study of its inhibition by branched chain fatty acids].

Rat brain succinic semialdehyde deshydrogenase has been purified 1300 fold. This enzyme is inhibited non competitively by the same branched chain fatty acids which inhibit GABA-transaminase competitively with respect to GABA. The respective activities of GABA-T and SSADH found in rat brain indicate that at anticonvulsant doses, the acids dipropylacetic and 2-methyl 2-ethyl caproic preferentially inhibit GABA-transaminase thus inducing a rise in cerebral GABA level. This increase is therefore not due to metabolism of the succinic semialdehyde by GABA-T.

4-Aminobutyrate Transaminase↗
PubMed1978

Purification and properties of two succinate semialdehyde dehydrogenases from human brain.

In human brain there are two major isoenzymes of succinate semialdehyde dehydrogenase (succinate-semialdehyde: NAD+ oxidoreductase, EC 1.2.1.24). They are composed of two apparently identical subunits with a molecular weight of 69 000. The Km (limits) for their substrates NAD+ and succinate semialdehyde are 1.6.10(-5) M and 3.7.10(-6) M, respectively, for one enzyme, and 1.85.10(-5) M and 2.10(-6) M, respectively, for the other. These values, and other kinetic data obtained from the two enzymes are not very different. However the enzymes differ in the following respects: their behavior on ion exchange and 5'-AMP affinity columns, their isoelectric points, their tryptic fingerprints and in their amino acid compositions.

Aldehyde Oxidoreductases↗
PubMed1989

Human brain glyceraldehyde-3-phosphate dehydrogenase, succinic semialdehyde dehydrogenase and aldehyde dehydrogenase isozymes: substrate specificity and sensitivity to disulfiram.

Several enzymes active in the presence of NAD with acetaldehyde and propionaldehyde have been purified from human brain and characterized. The enzymes have been identified as aldehyde dehydrogenase (EC 1.2.1.3), NAD-linked succinic semialdehyde dehydrogenase (EC 1.2.1.24), and glyceraldehyde-3-phosphate dehydrogenase (EC 1.2.1.12). Glyceraldehyde-3-phosphate dehydrogenase is extremely heterogeneous with some isozymes active with acetaldehyde, others inactive. The cytoplasmic enzyme, which is the classical glyceraldehyde-3-phosphate dehydrogenase, is inactive with acetaldehyde as substrate; the isozymes that are active with short chain aliphatic aldehydes are localized in the mitochondrial fraction. Properties of glyceraldehyde-3-phosphate dehydrogenase isozymes with respect to short chain aliphatic aldehydes and inhibition by disulfiram are described. Their Km values for acetaldehyde range from 300 to 2000 microM. All glyceraldehyde-3-phosphate dehydrogenases that are active with acetaldehyde are easily inactivated by low concentrations of disulfiram. In all cases activity regain can be obtained with 2-mercaptoethanol; in the case of two glyceraldehyde-3-phosphate isozymes (E8.5 and 9.0), activity can also be regained with cysteine and with glutathione; activity of E6.6 and E6.8 glyceraldehyde-3-phosphate dehydrogenases could not be regained with 33 microM cysteine or glutathione. Succinic semialdehyde dehydrogenase and aldehyde dehydrogenase (EC 1.2.1.3) were also inhibited by disulfiram; their activity could be regained with 2-mercaptoethanol but not with 33 microM cysteine or glutathione. Comparison of human brain succinic semialdehyde dehydrogenase and aldehyde dehydrogenase with glyceraldehyde-3-phosphate dehydrogenase shows that the activity with short chain aldehydes is not unique to aldehyde dehydrogenase; neither is sensitivity to disulfiram; activity with 3,4-dihydroxyphenylacetaldehyde appears to be a unique property of aldehyde dehydrogenase (EC 1.2.1.3).

Aldehyde Dehydrogenase↗
PubMed1986

GABA and circadian timekeeping: implications for manic-depression and sleep disorders.

Circadian rhythms, evident in a wide variety of physiological and behavioural parameters, are under the control of central neural pacemakers, the best characterized of which is the suprachiasmatic nucleus of the hypothalamus. The neurophysiological mechanisms involved in central pacemaker function are unknown. Recent biochemical, pharmacological and behavioural evidence suggests that the inhibitory transmitter gamma-aminobutyric acid (GABA), present in the small interneurones of the suprachiasmatic nucleus, plays an important role in circadian timekeeping. This has enabled the formulation of strategies for treatment of patients with manic depressive illness and certain sleep disorders in which disorders of circadian timekeeping may be fundamental.

4-Aminobutyrate Transaminase↗
PubMed1988

Pyritinol and the enzymes of gamma-aminobutyric acid (GABA) synthesis and degradation.

Pyritinol, a vitamin B6 derivative considered to have an activating effect on brain inhibited glutamate decarboxylase in concentrations of 0.05-1.0 mmol/l. This effect was not dependent on the pyridoxal-5'-phosphate concentration. An increase in the glutamate level reduced the inhibitory effect of pyritinol, but inhibition was not competitive. It is supposed that this modification of inhibition of glutamate decarboxylase by the substrate concentration might be associated with the presence of two glutamate decarboxylases with different affinities for the substrate. The inhibitory effect of pyritinol was dependent on integrity of the disulphide bond in the pyritinol molecule. Inhibition of glutamate decarboxylase increased in correlation to time--possibly in association with progressive oxidation of the SH-groups of the enzyme. Pyritinol did not influence GABA transaminase activity, but lessened the oxidation of GABA to carbon dioxide. It is assumed that succinic semialdehyde dehydrogenase activity was inhibited.

4-Aminobutyrate Transaminase↗
PubMed1992

Identification of human liver aldehyde dehydrogenases that catalyze the oxidation of aldophosphamide and retinaldehyde.

Biotransformation of the biologically and pharmacologically important aldehydes, retinaldehyde and aldophosphamide, is mediated, in part, by NAD(P)-dependent aldehyde dehydrogenases catalyze the oxidation of the aldehydes to their respective acids, retinoic acid and carboxyphosphamide. Not known at the onset of this investigation was which of the several known human aldehyde dehydrogenases (ALDHs) catalyze these reactions. Thus, human liver aldehyde dehydrogenases were chromatographically resolved and the ability of each to catalyze the oxidation of retinaldehyde and aldophosphamide was assessed. Only one, namely ALDH-1, catalyzed the oxidation of retinaldehyde; the Km value was 0.3 microM. Three, namely ALDH-1, ALDH-2 and succinic semialdehyde dehydrogenase, catalyzed the oxidation of aldophosphamide; Km values were 52, 1193, and 560 microM, respectively. ALDH-4, ALDH-5 and betaine aldehyde dehydrogenase did not catalyze the oxidation of either aldophosphamide or retinaldehyde. ALDH-1 and succinic semialdehyde dehydrogenase accounted for 64 and 30%, respectively, of the total hepatic aldehyde dehydrogenase-catalyzed aldophosphamide (160 microM) oxidation. ALDH-1-catalyzed oxidation of aldophosphamide was noncompetitively inhibited by chloral hydrate; the Ki value was 13 microM. ALDH-2- and succinic semialdehyde dehydrogenase-catalyzed oxidation of aldophosphamide was relatively insensitive to inhibition by chloral hydrate. These observations strongly suggest an important in vivo role for ALDH-1 in the catalysis of retinaldehyde and aldophosphamide biotransformation. Succinic semialdehyde dehydrogenase-catalyzed biotransformation of aldophosphamide may also be of some in vivo importance.

Adult↗
PubMed1990

Microphotometric determination of enzymes in brain sections. II. GABA transaminase.

The tetrazolium salt procedure of van Gelder (1965) for the demonstration of GABA transaminase (GABAT; the most important GABA degrading enzyme) was adapted for microphotometric measurements of GABAT activities in brain sections using the hippocampus of rats as selected brain region. The final incubation medium consisted of 50 mM GABA, 5 mM alpha-ketoglutarate, 7 mM NAD, 10 mM sodium azide, 6 mM nitroblue tetrazolium chloride, 20 mM malonate and 15% polyvinyl alcohol in 0.05 M Hepes buffer; the final pH was 8.0. There was a linear relationship between GABAT activity and section thickness up to 14 microns and between GABAT activity and reaction time at least up to 20 min (kinetic and end-point measurements). Phenazine methosulfate as an exogenous electron carrier and pyridoxal-5-phosphate as coenzyme of GABAT did not enhance the demonstrable GABAT activities, whereas sodium azide as a blocker of the respiratory chain resulted in an increase of demonstrable enzyme activities. A coreaction of succinate dehydrogenase was excluded by the use of malonate (competitive inhibitor). Using the incubation medium described GABAT activities were demonstrated via the endogenous enzymes succinic semialdehyde dehydrogenase and NADH tetrazolium reductase which were shown to be not rate limiting and seems to be similarly localized as GABAT.

4-Aminobutyrate Transaminase↗
PubMed1990

Molecular analysis of two genes of the Escherichia coli gab cluster: nucleotide sequence of the glutamate:succinic semialdehyde transaminase gene (gabT) and characterization of the succinic semialdehyde dehydrogenase gene (gabD).

We have characterized two genes of the Escherichia coli K-12 gab cluster, which encodes the enzymes of the 4-aminobutyrate degradation pathway. The nucleotide sequence of gabT, coding for glutamate:succinic semialdehyde transaminase (EC 2.6.1.19), alternatively known as 4-aminobutyrate transaminase, was determined. The structural gene consists of 1,281 nucleotides specifying a protein of 426 amino acids with a molecular mass of 45.76 kDa. The protein shows significant homologies to the ornithine transaminases from Saccharomyces cerevisiae and from rat and human mitochondria. Three functionally and structurally important amino acid residues of the transaminase were identified by sequence comparison studies, and evolutionary relationships of the aminotransferases are discussed. The gabD gene, encoding succinic semialdehyde dehydrogenase (EC 1.2.1.16), was cloned and shown to be located adjacent to the 5' end of gabT. Expression studies with subfragments of the initially cloned DNA region revealed a maximal size of 1.7 kb for gabD. Both genes are cotranscribed from a promoter located upstream of gabD.

4-Aminobutyrate Transaminase↗
PubMed1992

Inactivation of gamma-aminobutyric acid aminotransferase by various amine buffers.

It is hypothesized that buffers capable of forming a Schiff base with the PLP of gamma-aminobutyric acid aminotransferase (GABA-AT) may lead to denaturation and inactivation of the enzyme. On the basis of this hypothesis three new methods for the selective destruction of GABA-AT in GABAse (a commercial bacterial source of a mixture of GABA-AT and succinic semialdehyde dehydrogenase [SSDH]) and from pig brain are described: (1) dialysis against a primary or secondary amine buffer; (2) gel filtration with a primary or secondary amine buffer as eluent; (3) inactivation with gabaculine followed by dialysis or gel filtration with pyrophosphate buffer. The SSDH activity in GABAse, which remains unchanged by all of these methods, may then be used in a coupled assay to measure the activity of GABA-AT from different sources. These results also suggest that the use of primary and secondary amine buffers should be avoided when inhibitors are being tested with GABA-AT.

4-Aminobutyrate Transaminase↗
PubMed2024

Clinical features and ALDH5A1 gene findings in 13 Chinese cases with succinic semialdehyde dehydrogenase deficiency.

BACKGROUND AND AIMS: To investigate the clinical features, ALDH5A1 gene variations, treatment, and prognosis of patients with succinic semialdehyde dehydrogenase (SSADH) deficiency. MATERIALS AND METHODS: This retrospective study evaluated the findings in 13 Chinese patients with SSADH deficiency admitted to the Pediatric Department of Peking University First Hospital from September 2013 to September 2023. RESULTS: Thirteen patients (seven male and six female patients; two sibling sisters) had the symptoms aged from 1 month to 1 year. Their urine 4-hydroxybutyrate acid levels were elevated and were accompanied by mildly increased serum lactate levels. Brain magnetic resonance imaging (MRI) showed symmetric abnormal signals in both sides of the globus pallidus and other areas. All 13 patients had psychomotor retardation, with seven showing epileptic seizures. Among the 18 variants of the ALDH5A1 gene identified in these 13 patients, six were previously reported, while 12 were novel variants. Among the 12 novel variants, three (c.85_116del, c.206_222dup, c.762C > G) were pathogenic variants; five (c.427delA, c.515G > A, c.637C > T, c.755G > T, c.1274T > C) were likely pathogenic; and the remaining four (c.454G > C, c.479C > T, c.1480G > A, c.1501G > C) were variants of uncertain significance. The patients received drugs such as L-carnitine, vigabatrin, and taurine, along with symptomatic treatment. Their urine 4-hydroxybutyric acid levels showed variable degrees of reduction. CONCLUSIONS: A cohort of 13 cases with early-onset SSADH deficiency was analyzed. Onset of symptoms occurred from 1 month to 1 year of age. Twelve novel variants of the ALDH5A1 gene were identified.

Child, Preschool↗
PubMed1990

In vivo cloning and characterization of the gabCTDP gene cluster of Escherichia coli K-12.

The gabCTDP gene cluster, which specifies and regulates synthesis of the gamma-aminobutyrate (GABA) transport carrier, of glutamate-succinic semialdehyde transaminase, and of succinic semialdehyde dehydrogenase, responsible for the uptake and metabolism of gamma-aminobutyric acid in Escherichia coli K-12, was cloned in vivo, using the mini-Mu replicon bacteriophage Mu dI5086 as the vector. A subclone containing a 7.8-kilobase (kb) EcoRI-HindIII fragment complemented all of our Gab- mutants. By restriction mapping, this DNA fragment was located at kb 2800.5 to 2808.5 on the physical map of the E. coli K-12 chromosome. A subclone containing a 1.8-kb EcoRI-SalI fragment complemented the gab-repressed strain CS101A (wild-type gabC) but did not complement any gab structural gene mutants. The gab genes are divergently transcribed from promoters located in the vicinity of the unique BamHI site. Transcription in both directions is under dual control of catabolite repression and nitrogen regulation. Using a procaryotic DNA-directed translation system, we observed three insert-coded polypeptide bands of 53 to 55, 45 to 48, and 40 to 43 kilodaltons (kDa). In vivo studies with subcloned fragments of the gab DNA identified the 53- to 55- and 45- to 48-kDa bands as products of the BamHI-SalI fragment and the 40- to 43-kDa band as the product of the EcoRI-SalI fragment. An additional 26- to 28-kDa band was identified as the product of the BamHI-HindIII fragment. Furthermore, the BamHI-SalI fragment was shown to specify synthesis of the two GABA enzymes, whereas synthesis of the GABA carrier was specified by the BamHI-HindIII fragment. No catalytic function in addition to its regulatory role could be attributed to the EcoRI-SalI gene product.

Aldehyde Oxidoreductases↗
PubMed1989

Potato tuber succinate semialdehyde dehydrogenase: purification and characterization.

Succinate semialdehyde dehydrogenase (SSADH) has been purified from potato tubers with 39% yield, 832-fold purification, and a specific activity of 6.5 units/mg protein. The final preparation was homogeneous as judged from native and sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Gel filtration on Sepharose 6B gave a relative molecular mass (Mr) of 145,000 for the native enzyme. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis gave a single polypeptide band of Mr 35,000. Thus the enzyme appears to be a tetramer of identical subunits. Chromatofocusing of the enzyme gave a pI of 8.7. The enzyme was maximally active at pH 9.0 in 100 mM sodium pyrophosphate buffer. In 100 mM Tris-HCl buffer, pH 9.0, the enzyme gave only 20% of the activity found in pyrophosphate buffer and had a shorter linear rate. The enzyme was specific for succinate semialdehyde (SSA) as substrate and could not utilize acetaldehyde, glyceraldehyde 3-phosphate, malonaldehyde, lactate, or ethanol as substrates. The enzyme was also specific for NAD+ as cofactor and NADP+ and 3-acetylpyridine adenine dinucleotide could not serve as cofactors. Potato SSADH had a Km of 4.6 microM for SSA when assayed in pyrophosphate buffer and was inhibited by that substrate at concentrations greater than 120 microM. The Km for NAD+ was found to be 31 microM. The enzyme required exogenous addition of a thiol compound for maximal activity and was inhibited by the thiol-directed reagents p-hydroxymercuribenzoate, dithionitrobenzoate, and N-ethyl-maleimide, by heavy metal ions Hg2+, Cu2+, Cd2+, and Zn2+, and by arsenite. These results indicate a requirement of a SH group for catalytic activity.

Aldehyde Oxidoreductases↗
PubMed1992

Succinic semialdehyde dehydrogenase from mammalian brain: subunit analysis using polyclonal antiserum.

1. NAD(+)-dependent succinic semialdehyde dehydrogenase was purified to apparent homogeneity from rat brain and highly purified from human brain. 2. Molecular exclusion chromatography of the purified enzymes on Sephadex G-150 and G-200 revealed M(r) values of 203,000 and 191,000 for rat and human, respectively. 3. Electrophoresis on sodium dodecylsulfate polyacrylamide gels revealed a single subunit of M(r) 54,000 for rat and 58,000 for human. Isoelectric focusing of the purified rat enzyme yielded a pI of 6.1. 4. For both proteins, Km values for short-chain aldehydes acetaldehyde and propionaldehyde ranged from 0.33 to 2.5 mM; Km values for succinic semialdehyde were in the 2-4 microM range. 5. The subunit structure of both enzymes was investigated in brain extracts and purified preparations by immunoblotting, using a polyclonal rabbit antiserum against the purified rat brain enzyme. 6. For rat and human extracts, single bands were detected at M(r) 54,000 and 58,000, comparable to findings in the purified preparations. Immunoblotting analyses in other species (guinea pig, hamster, mouse and rabbit) revealed single subunits of M(r) 54,000-56,500.

Aldehyde Oxidoreductases↗