Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.6.1.19 (GABA transaminase)
 808 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The carbonyl reagent amino-oxyacetate is frequently used in metabolic studies to inhibit individual pyridoxal phosphate enzymes. The reaction of this compound with three such enzymes, aspartate transaminase, 4-aminobutyrate transaminase and dopa (3,4-dihydroxyphenylalanine) decarboxylase, was studied to determine the extent to which the inhibition is reversible and the rates at which it takes place. Reactions were followed by observing changes in the absorption spectra of the bound coenzyme and by measuring loss of enzyme activity. The reactions with aspartate transaminase and aminobutyrate transaminase were not rapidly reversible and had second-order rate constants (21 degrees C) of 400 M-1.s.1 and 1300 M-1.s-1 respectively and all all concentrations studied showed the kinetics of a simple bimolecular reaction. The reaction with 4-aminobutyrate transaminase could not be reversed and that with aspartate transaminase could only be reversed significantly by addition of cysteinesulphinate to convert the enzyme into its pyridoxamine form. The first-order rate constant (21 degrees C) for the reverse reaction was 4 X 10(-5)s-1. Dopa decarboxylase inhibition by amino-oxyacetate was more rapid and more readily reversible, but measurements of rate and equilibrium constants were not obtained for this enzyme.
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PMID:The reaction of amino-oxyacetate with pyridoxal phosphate-dependent enzymes. 66 36

Gabaculine, a specific inhibitor of GABA transaminase, was injected bilaterally into the substantia nigra of rats. One day after injection, GABA was increased 11-fold in the nigra, 6-fold in thalamus and pons-medulla, and 2-fold in pallidum. 5 h after operation, rats showed continuous sniffing and head movement. This behaviour was blocked by a small dose of picrotoxin injected bilaterally into the nigra, but haloperidol (i.p.) was less effective. One day after injection, rats showed high ambulation and this ambulation was blocked by high doses of picrotoxin. On the second day, GABA contents in all regions were less than twice the control level and behaviour had returned to normal. Rats with gabaculine injected into the pallidum or medulla did not show changes of behaviour as seen in rats with injections into the substantia nigra at any of the times. Striatum dopamine turnover was slightly but significantly decreased at 5 h but not at 24 h after intra-nigral injection with gabaculine. The results suggest that gabaculine-induced sniffing and head movement were mediated by nigral GABAergic synapses and were independent of any dopaminergic system, and that the high ambulation at 24 h after operation may have been due to a non-specific effect of abnormal GABA elevation in thalamus and/or nigra.
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PMID:The effects of elevating gamma-amino butyrate content in the substantia nigra on the behaviour of rats. 68 78

The correlation between the gamma-aminobutyric acid (GABA) metabolism and convulsions by some vitamin B6 antagonists, DL-penicillamine (PeA), hydrazine (Hyd), thiosemicarbazide (TSC) were investigated. Glutamic acid decarboxylase (GAD) and gamma-aminobutyric acid transaminase (GABA-T) activities were inhibited during convulsions by three antagonists, and GABA content was not changed by PeA, increased by Hyd and decreased by TSC in mice whole brain. In subcellular fractions of brain, GAD activity was inhibited and GABA content decreased in synaptosomes during convulsions by the above three drugs. Aminooxyacetic acid (AOAA), a potent GABA-elevating agent, showed an anticonvulsant property against convulsions by TSC for several hours after the injection of AOAA, but lost this property 16hr after treatment. During the convulsions by TSC 16hr after the AOAA-pretreatment, the GABA content in synaptosomes was less than that from the group treated with AOAA alone, though its GABA level was higher than the normal level. From the above results, the GABA content and GAD activity in synaptosomes might be deeply associated with convulsions by B6 antagonists.
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PMID:Relationship between gamma-aminobutyric acid metabolism and antivitamin B6-induced convulsions. 71 35

The RMI, an irreversible inhibitor of GABA transaminase, inhibited, at the dose of 100 mg/kg, the activity of Mice placed in an open-field. At lower doses, RMI improved the activity in open-field and the number of conditioned avoidance reactions. Results are correlated with increase of the level of brain GABA, following administration of RMI.
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PMID:[Effect of an irreversible inhibitor (RMI71645) of gamma-aminobutyric acid (GABA) transaminase on spontaneous and conditioned activities of mice]. 82 60

N-(5'-Phosphophopyridoxyl)-4-aminobutyric acid, a stable adduct of pyridoxal phosphate and 4-aminobutyrate acid, has been shown to be a potent inhibitor of rat brain 4-aminobutyric acid aminotransferase (GABA-T) with a K1 of 1.4 muM.
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PMID:N-(5'-Phosphopyridoxyl)-4-aminobutyric acid: a stabel bisubstrate adduct inhibitor of rat brain 4-aminobutyric acid aminotransferase. 83 10

In order to determne the intramitochondrial location of 4-aminobutyrate transaminase, mitochondria were prepared from ox brain and freed from myelin and synaptosomes by using conventional density-gradient-centrifugation techniques, and the purity was checked electron-microscopically. Inner and outer membranes and matrix were prepared from the mitochondria by large-amplitude swelling and subsequent density-grient centrifugation. The fractions were characterized by using both electron microscopy and different marker enzymes. From the specific activity of the 4-aminobutyrate transaminase in the submitochondrial fractions it was concluded that this enzyme is associated with the innter mitochondrial membrane.
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PMID:Intramitochondrial localization of the 4-aminobutyrate-2-oxoglutarate transaminase from ox brain. 84 86

Incubation of rat brain 4-aminobutyrate aminotransferase with 4-amino-hex-5-enoic acid, a substrate analog of 4-aminobutyric acid, results in a time-dependent irreversible loss of enzymatic activity. In the presence of 0.1 mM inhibitor the half-life of the inactivation process is approximately 6 min. Low concentrations of L-glutamic acid or 4-aminobutyric acid protect against this inactivation, while 2-oxoglutarate prevents this protection, suggesting that only the pyridoxal form of the enzyme is susceptible to inhibition by 4-amino-hex-5-enoic acid. The irreversible inhibition of mammalian 4-aminobutyrate aminotransferase by 4-amino-hex-5-enoic acid is selective. There is no inhibition of this enzyme from Pseudomonas fluorescens with the inhibitor at mM concentrations. Even at 10 mM there is no irreversible inhibition of mammalian glutamate decarboxylase or of aspartate aminotransferase, while alanine aminotransferase is inhibited over 500 times more slowly than rat brain 4-aminobutyrate transaminase.
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PMID:4-amino-hex-5-enoic acid, a selective catalytic inhibitor of 4-aminobutyric-acid aminotransferase in mammalian brain. 85 82

In the belief that homocysteine-induced convulsions might be related to alterations in brain gamma-aminobutyric acid metabolism, we have studied the action of this amino acid on the activity of glutamic decarboxylase (GAD, EC 4.1.1.15) and gamma-aminobutyrate aminotransferase (EC 2.6.1.19) of mouse brain in vitro DL-homocysteine competitively inhibited GAD with respect to both L-glutamate and pyridoxal 5'-phosphate. The respective Ki's were 3.8 mM and 0.3 mM. The activity of GABA-T also was altered in the presence of DL-homocysteine. A competitive inhibition (Ki = 6 mM) was observed with gamma-aminobutyric acid, and an uncompetitive inhibition with respect to pyridoxal 5'-phosphate and alpha-ketoglutarate. These results are explained in terms of a dual action of homocysteine on each of the enzymes: one involving a competition for substrate binding site and the other involving the formation of an inactive inhibitor-cofactor complex. The significance of the inhibition of these enzymes of gamma-aminobutyric acid metabolism is discussed in relation to the convulsant action of homocysteine.
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PMID:The mode of action of homocysteine on mouse brain glutamic decarboxylase and gamma-aminobutyrate aminotransferase. 90 1

Two clinically effective anticonvulsants, phenobarbitone and diazepam, protected 5-day old chicks against picrotoxin convulsions without reducing brain GABA-transaminase activity or raising brain GABA concentration. Ethanolamine-O-sulphate and amino-oxyacetic acid, in doses which inhibited GABA-transminase by at least 63% and approximately doubled brain GABA concentration, did not significantly affect the ED50 for picrotoxin convulsions. The ED50 for picrotoxin convulsions was significantly raised by di-n-propylacetate (800 mg/kg) which inhibited GABA transaminase activity by 6% and elevated brain GABA concentration by 26%.
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PMID:Picrotoxin convulsions and GABA metabolism after injection of anticonvulsants in chicks. 99 20

The study of interaction of 4-aminobutyrate transaminase with 5'- 6'-methyl derivates of PLP demonstrated that only the former was capable of forming a catalytically active holoenzyme possessing 0.37 activity of the native holoenzyme and a low affinity substrates. This compound interacts with the apoenzyme at a slower rate than does PLP; it has a reduced affinity towards apotransaminase (Km = 1.10(-4) M) and is replaced from the active site by native coenzyme. The other analog of pyridoxal-5'-phosphate forms a catalytically inactive complex with the apoenzyme; the other analog is not replaced from the active center by native coenzyme and non-competitively inhibits the reconstruction of apotransaminase (Ki = 2.10(-5) M).
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PMID:[Interaction of 4-aminobutyrate-transaminase from swine kidneys with 5'- and 6'-methyl derivatives of pyridoxal-5'-phosphate]. 99 79


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