Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P80404 (GABA transaminase)
 786 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Bacillus cereus strain K-22 produced two distinct omega-amino acid transaminases, one catalyzing the transamination between beta-alanine and pyruvic acid and the other that between gamma-aminobutyric acid and alpha-ketoglutaric aic. The two enzymes were partially purified and separated from each other by various chromatographies. beta-Alanine:pyruvic acid transaminase and gamma-aminobutyric acid:alpha-ketoglutaric acid transaminase were induced by the addition of beta-alanine and gamma-aminobutyric acid, respectively, to the growth medium. beta-Alanine transaminase showed an optimum pH of 10.0 and optimum temperature of 35 degrees C, and its Km values for beta-alanine and pyruvic acid were both 1.1 mM. gamma-Aminobutyric acid, epsilon-aminocaproic acid, 2-aminoethylphosphonic acid, and propylamine showed about 30-40% of the activity of beta-alanine as amino donors, and oxalacetic acid was as good an amino acceptor as pyruvic acid. The optimum pH and temperature of gamma-aminobutyric acid transaminase were 9.0 and 50 degrees C, respectively, and its Km value for gamma-aminobutyric acid was 2.8 mM, while that for alpha-ketoglutaric acid was 2.3 mM. gamma-Aminobutyric acid and delta-aminovaleric acid were good amino donors but other omega-amino acids were virtually inactive with gamma-aminobutyric acid transaminase; alpha-ketoglutaric acid, and to a lesser extent glyoxylic acid, were active amino acceptors. Sulfhydryl reagents specifically activated gamma-aminobutyric acid transaminase.
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PMID:Two omega-amino acid transaminases from Bacillus cereus. 1 32

Three unlinked genes where mutation can lead to D(+)-pantothenic acid auxotrophy in Aspergillus nidulans have been identified. pantoA is probably the structural gene for pantothenate synthetase (EC 6.3.2.1) whilst pantoB and pantoC are involved in the syntheses of D-pantoic acid and beta-alanine, respectively. A pantoC- mutant is tentatively considered to be blocked in conversion of 5,6-dihydrouracil to beta-ureidopropionate. An alternative route of beta-alanine biosynthesis occurs by the transamination of malonic semialdehyde, catalysed by GABA transaminase. The possibility that beta-alanine can be replaced by certain structurally related compounds and yet nevertheless yield biologically active coenzyme A analogues is discussed.
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PMID:GABA transaminase provides an alternative route of beta-alanine synthesis in Aspergillus nidulans. 35 40

Gabaculine, 5-amino-1,3-cyclohexadienylcarboxylate, is an analogue of GABA and a potent irreversible inhibitor of GABA aminotransferase. However, D-3-aminoisobutyrate-pyruvate aminotransferase for which GABA was neither a substrate nor an inhibitor was also inactivated by gabaculine. The Ki for D-3-aminoisobutyrate-pyruvate aminotransferase was 8.3 x 10(-6) M, and the Kcat for its turnover was 0.31 min-1 at 25 degrees C. beta-Alanine protected the enzyme from inactivation by gabaculine, but GABA did so to much a lesser extent.
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PMID:Irreversible inhibition of D-3-aminoisobutyrate-pyruvate aminotransferase by gabaculine. 212 4

Slices of rat temporo-parietal cortex were prelabeled with gamma-[3H]aminobutyric acid ([3H]GABA), in the presence of the glial GABA uptake inhibitor beta-alanine. The slices were then superfused with a medium containing the GABA transaminase inhibitor aminooxyacetic acid and stimulated electrically (5 min, 2 msec, 36 mA at 5 or 10 Hz), in the presence of the neuronal GABA reuptake inhibitor SK&F 89976A [N-(4,4-diphenyl-3-butenyl)-nipecotic acid] and of beta-alanine. Representative experiments showed that the tritium released could be accounted for almost entirely by authentic [3H]GABA. The electrically evoked overflow of [3H]GABA was tetrodotoxin sensitive and largely calcium-dependent. Exogenous GABA, added to the superfusion medium at 3 to 30 microM, reduced in a concentration-dependent manner the electrically evoked (5 Hz) release of [3H]GABA. The GABAB receptor agonist (-)-baclofen, but not the GABAA receptor agonist muscimol, mimicked GABA and produced a concentration-inhibition curve almost superimposable to that of the natural transmitter. The effects of GABA and of (-)-baclofen were much more pronounced at 5 than at 10 Hz. The GABA-induced inhibition of [3H]GABA release was sensitive to the novel GABAB receptor antagonist beta-(p-chlorophenyl)-3-amino propyl phosphonic acid which, by itself, increased the [3H]GABA overflow. The inhibitory effect of GABA was not counteracted by the GABAA receptor antagonists bicuculline or SR 95531 [2-(3'-carbethoxy-2'-propenyl)-3-amino-6-paramethoxy-phenyl-pyr idazinium bromide]. The results are compatible with the presence in the rat cerebral cortex of autoreceptors mediating inhibition of GABA release and belonging to the GABAB type. These autoreceptors may be activated tonically under physiological conditions.
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PMID:Release of gamma-[3H]aminobutyric acid (GABA) from electrically stimulated rat cortical slices and its modulation by GABAB autoreceptors. 254 42

Because of the importance of the inactivation of GABA aminotransferase to the design of anticonvulsant agents, a seemingly wide variety of inactivators has been investigated; all of the compounds, however, are analogues of GABA, beta-alanine, or delta-aminovaleric acid, which are substrates for the enzyme. Relatively minor modifications in the inactivator structures result in major differences in inactivation mechanisms and enzyme adduct structures. Compounds that inactivate GABA aminotransferase by a Michael addition mechanism, leading to modification of an active-site residue are Class I inactivators. Those that proceed by an enamine mechanism and give ternary adducts are Class II inactivators. Class III inactivators modify only the PLP cofactor; if the inactivation involves aromatization of the inactivator, it is a Class IIIA inactivation, and if no aromatization is involved, then it is a Class IIIB inactivation. The last class of inactivators (Class IV) are not classified on the basis of the mechanism, but, rather, that they require the enzyme to be in the PMP form. There appears to be no trend in partition ratio values when comparing Class I with Class II inactivators. Class III inactivations alter only the cofactor, so it may be possible for these adducts to diffuse slowly out of the active site; reactivation of the apoenzyme would require additional PLP. These inactivators also inactivate a variety of other PLP-dependent enzymes. At this point there does not seem to be a therapeutic advantage of one class of inactivators over another, although the only current example of these inactivators to be useful clinically is gamma-vinyl GABA (vigabatrin), a Class I inactivator recently approved for the drug market in France and the U.K. There is a mechanistic significance, however, for one class over another. If labeling of an active-site amino acid residue is desired, then Class I inactivators should be selected; desire for attachment of the inactivator to both the protein and the cofactor or just to the cofactor would determine whether Class II or Class III inactivators would be chosen. The classification presented here should allow us to think about inactivator structures in terms of their mechanistic potential and, as a result of this, should afford us the opportunity to be able to make predictions regarding inactivation mechanisms for hypothetical new structural classes of inactivators. Since the different mechanistic pathways lead to different types of enzyme adducts, inactivator design may be driven by the class of adduct that is desired.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Design of potential anticonvulsant agents: mechanistic classification of GABA aminotransferase inactivators. 268 82

beta-Difluoromethyl-beta-alanine (3-amino-4,4-difluorobutanoic acid) is a potent in vitro and in vivo inhibitor of GABA-T. The rate of inhibition of GABA-T is concentration- and time-dependent. The inactivation is active-site directed. No reactive species escapes from the active site before reacting with the enzyme. The inhibition is irreversible and stereospecific. The use of beta-2H-beta-difluoromethyl-beta-alanine results in a marked primary isotope effect in vitro and in vivo. The use of differently substituted dihalogeno derivatives of beta-alanine suggests that the rate of inhibition is dependent on the nature and position of the leaving group. The mechanism of inhibition is discussed on the basis of spectral changes.
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PMID:Irreversible inhibition of GABA-T by halogenated analogues of beta-alanine. 315 Apr 30

Antinociception produced by the GABA uptake inhibitors d,l- SKF-89976A and SKF-100330A was characterized and compared to that produced by other types of GABAergic drugs. Using the mouse tail-immersion assay it was found that the antinociception produced by the uptake inhibitors was antagonized by scopolamine, a cholinergic muscarinic receptor antagonist. However, neither SKF compound demonstrated any significant affinity for muscarinic receptor binding sites suggesting that they are not direct-acting cholinomimetics. In vitro uptake experiments revealed that the SKF compounds selectively inhibit GABA transport, having no effect on the accumulation of aspartic acid, glutamic acid, beta-alanine or glycine. Moreover, antinociception and GABA uptake inhibition were stereoselective for SKF-89976A, with the d-isomer being more active in both tests. When comparing antinociceptive responses at maximally effective doses it was also found that the SKF compounds were substantially more efficacious than direct-acting GABA receptor agonists or a GABA transaminase inhibitor. These data suggest that uptake inhibitors may be facilitating GABA transmission in a system that is less affected by other types of GABAergic compounds.
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PMID:GABA uptake inhibitors produce a greater antinociceptive response in the mouse tail-immersion assay than other types of GABAergic drugs. 405 59

The anticonvulsant effect of inhibitors of GABA-T (R/S-gamma-vinyl-GABA, ethanolamine-O-sulfate, gabaculine, aminooxyacetic acid) was enhanced by 10 mmol/kg glycine in animal seizure models which are based on a functional GABA deficit. Similar to glycine in their action, although less effective, were its close structural analogues (sarcosine, N,N-dimethylglycine) and homologous omega-aminoacids (beta-alanine, taurine, gamma-aminobutyric acid, delta-aminovaleric acid). It is assumed that glycine and its structural analogues act on supraspinal glycine receptors as glycine agonists. Our observation is the first example of the synergistic interaction of two inhibitory neuronal systems resulting in the amplification of the anticonvulsant effect. Combined treatment with GABA-T inhibitors and glycine may turn out to be of practical importance in the therapy of seizure disorders and other diseases, for which treatment with GABA-T inhibitors is considered a potentially useful therapeutic approach.
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PMID:Synergistic anticonvulsant effects of GABA-T inhibitors and glycine. 647 85

omega-Monofluoromethyl and omega-difluoromethyl analogues of the known substrates of GABA-T, beta-alanine, gamma-aminobutyric acid, and 5-aminopentanoic acid, are time-dependent inhibitors of purified 4-aminobutyrate: 2-oxoglutarate aminotransferase (GABA-T). The inhibitory activity decreases with increasing chain length. In vitro, inhibitory activity decreases with increasing fluorine substitution of the methyl group. In vivo, beta-difluoromethyl-beta-alanine and 2,4-difluoro-3-aminobutyric acid are the most potent GABA-T inhibitors ever reported. Trifluoromethyl derivatives are devoid of GABA-T inhibitory activity in vitro or in vivo.
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PMID:omega-Fluoromethyl analogues of omega-amino acids as irreversible inhibitors of 4-aminobutyrate:2-oxoglutarate aminotransferase. 679 12

1. Two methods have been devised for the detection after electrophoresis of gamma-aminobutyric acid transaminase (GABAT) isozymes. 2. GABAT isozymes can be detected in liver, brain, kidney, pancreas, heart, testis. spinal cord and upper jejunum. The greatest activity occurs in liver. 3. Three different commonly occurring electrophoretic types of GABAT have been identified. It seems likely that they are determined by two alleles at an autosomal locus (GABAT). 4. The gene frequencies of GABAT1 and GABAT2 in a random sample of European livers were 0.56 and 0.44 respectively. 5. The three banded patterns seen in heterozygotes suggest that GABAT is a dimeric enzyme. 6. GABA, beta-alanine and 5-aminovaleric acid can act as substrates for GABAT. 7. GABAT activity can be demonstrated in all areas of human brain with the exception of the corpus callosum. Brain samples from patients with Huntington's chorea show no abnormal GABAT activity or unusual phenotypes.
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PMID:The biochemical genetics of human gamma-aminobutyric acid transaminase. 730 80


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