Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.6.1.19 (GABA transaminase)
808 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A state of the gamma-aminobutyric acid (GABA) system (glutamate, glutamate decarboxylase, GABA, GABA-alpha-ketoglutarate aminotransferase) and the coupled reactions (alpha-ketoglutarate dehydrogenase complex, aspartate- and alanine aminotransferases) was studied in three brain structures (cerebellum, brain cortex and truncus cerebri) after multiple administration of pyridoxal-5'-phosphate (PALP) and its Shiff base with GABA (5 injections at doses 10.0 and 15.0 mg/kg of body mass, respectively). Non-coenzymatic effects of PALP were found to prevail within 1 hr after its last administration: inhibition of PALP-dependent aminotransferases and activation of the alpha-keto-glutarate oxidative decarboxylation were observed. The opposite effects were detected after addition of PALP to brain homogenates in vitro. Administration of the PALP-GABA complex exhibited qualitatively similar to those of PALP effects on the reactions studied in brain. The data obtained suggest that parenteral administration of the coenzyme preparation caused a number of metabolic effects, which are sometimes far from unambigously predicted theoretical considerations. The similarity of PALP and PALP-GABA effects appears to demonstrate ready biotransformation of the Shiff base with liberation of PALP and GABA.
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PMID:[Changes in the brain GABA system after repeated injections of pyridoxal-5'-phosphate and its Schiff base with GABA]. 274 11

The nucleotide ATP was shown to be a reversible inhibitor of partially purified gamma-aminobutyrate aminotransferase isolated from mouse brain. This inhibition was of the competitive type with respect to the substrate, gamma-aminobutyric acid (Ki = 3.7 +/- 0.6 mM), but was noncompetitive with respect to both the second substrate alpha-ketoglutarate and the cofactor pyridoxal 5'-phosphate. Two analogues of ATP, ADP and GTP, also gave rise to an inhibition gamma-aminobutyrate aminotransferase that was similar to that produced by ATP. These results are consistent with the view that mouse brain gamma-aminobutyric acid aminotransferase could be under regulatory control by ATP and certain other nucleotides within the mitochondria.
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PMID:Competitive inhibition of mouse brain gamma-aminobutyrate aminotransferase by ATP. 279 33

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.
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PMID:Pyritinol and the enzymes of gamma-aminobutyric acid (GABA) synthesis and degradation. 297 3

Evidence for an enamine mechanism of inactivation of pig brain gamma-aminobutyric acid (GABA) aminotransferase by (S,E)-4-amino-5-fluoropent-2-enoic acid is presented. apo-GABA aminotransferase reconstituted with [3H]pyridoxal 5'-phosphate is inactivated by (S,E)-4-amino-5-fluoropent-2-enoic acid and the pH is raised to 12. All of the radioactivity is released from the enzyme as an adduct of the cofactor; no [3H]pyridoxamine 5'-phosphate is generated.
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PMID:Mechanism of inactivation of gamma-aminobutyric acid aminotransferase by (S,E)-4-amino-5-fluoropent-2-enoic acid. 334 72

(Z)-4-Amino-2-fluorobut-2-enoic acid (1) is shown to be a mechanism-based inactivator of pig brain gamma-aminobutyric acid aminotransferase. Approximately 750 inactivator molecules are consumed prior to complete enzyme inactivation. Concurrent with enzyme inactivation is the release of 708 +/- 79 fluoride ions; transamination occurs 737 +/- 15 times per inactivation event. Inactivation of [3H]pyridoxal 5'-phosphate ([3H]PLP) reconstituted GABA aminotransferase by 1 followed by denaturation releases [3H]PMP with no radioactivity remaining attached to the protein. A similar experiment carried out with 4-amino-5-fluoropent-2-enoic acid [Silverman, R. B., Invergo, B. J., & Mathew, J. (1986) J. Med. Chem. 29, 1840-1846] as the inactivator produces no [3H]PMP; rather, another radioactive species is released. These results support an inactivation mechanism for 1 that involves normal catalytic isomerization followed by active site nucleophilic attack on the activated Michael acceptor. A general hypothesis for predicting the inactivation mechanism (Michael addition vs enamine addition) of GABA aminotransferase inactivators is proposed.
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PMID:Inactivation of gamma-aminobutyric acid aminotransferase by (Z)-4-amino-2-fluorobut-2-enoic acid. 339 Apr 32

Biochemical and pharmacological effects of gamma-vinyl GABA (Vigabatrin, GVG), and irreversible enzyme-activated inhibitor of 4-aminobutyrate: 2-oxoglutarate aminotransferase (EC 2.6.1.19; GABA-T), were measured in mice. This anticonvulsant produced a time- and dose-dependent elevation of the GABA, phenylalanine and lysine contents of cortical tissue and simultaneously decreased glutamate, aspartate and alanine levels. In addition, GVG caused a biphasic change in glutamine concentrations (a decline 1-4 hours after administration, followed 20 hours later by an increase). Moreover, we found a new, as yet unidentified amino acid in the brain eluting with the same retention time as alpha-aminoadipic acid from an HPLC cation-exchange column. The level of this novel chemical entity was greatly increased by GVG 20 hours after injection of the drug. At all tested intervals between 1 and 60 hours after injection, GVG was ineffective against maximal electroshock. The GABA-T inhibitor dose-dependently protected mice against isoniazid-induced seizures, simultaneously causing an increase in brain GABA concentrations. However, this apparent correlation applied only until 4 hours after treatment. To better define the anticonvulsant profile of GVG, groups of mice were treated, 1, 2, 4, and 24 hours prior to challenge with convulsant doses of strychnine, pentetrazole (PTZ), and picrotoxin, and brain amino acid levels, including brain concentrations of GVG, were measured. In all instances, the time dependency of the anticonvulsant effects of GVG and of increases in brain GABA levels differed. Amino acid concentrations in animals treated only with GVG were similar to those in animals given GVG and a chemical convulsant. GVG showed no selectivity for seizures produced by impairment of GABA-ergic neurotransmission. Although GVG is an effective GABA-T inhibitor, it apparently affects several other pyridoxal-phosphate-dependent cerebral enzymes and/or interacts with other neurotransmitter systems as well.
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PMID:Gamma-vinyl GABA: comparison of neurochemical and anticonvulsant effects in mice. 341 34

4-Aminobutyrate aminotransferase is inactivated by preincubation with iodosobenzoate at pH 7. The reaction of 2 SH residues/dimer resulted in formation of an oligomeric species of Mr = 100,000 detectable by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The subunits cross-linked via a disulfide bond are dissociated by addition of 2-mercaptoethanol which also restores full catalytic activity (Choi, S. Y., and Churchich, J.E. (1985) J. Biol. Chem. 260, 993-997). The substrate 2-oxoglutarate prevents inactivation of the enzyme by iodosobenzoate and the subsequent formation of one disulfide bond, whereas 4-aminobutyrate has no effect on the reactivity of SH groups with iodosobenzoate. Modified 4-aminobutyrate aminotransferase (containing 1 disulfide bond) catalyzes a half-transamination reaction; but it is unable to react with 2-oxoglutarate to generate the aldimine form of the enzyme. The spectroscopic properties (fluorescence yield and polarization of fluorescence) of PMP bound to the modified enzyme are different from those of pyridoxamine phosphate (PMP) bound to the native enzyme. The polarization of fluorescence values of PMP bound to the cross-linked enzyme, excited over the spectral range 310-370 nm, are greater (25%) than those of the cofactor of the native enzyme. An increase in the polarization values implies that the motion of PMP is restricted when the subunits are cross-linked via a disulfide bond.
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PMID:The reversible oxidation of vicinal SH groups in 4-aminobutyrate aminotransferase. Probes of conformational changes. 365 61

Highly purified 4-aminobutyrate aminotransferase from pig brain is susceptible to phosphorylation by the purified cAMP-dependent protein kinase catalytic subunit. Up to 0.7 moles of phosphate from ATP-(gamma)-32P can be incorporated per mole of dimeric holoenzyme. Maximum phosphorylation was observed within about 90 minutes at 30 degrees C. Despite the extensive degree of phosphorylation observed, no kinetic property of the enzyme was perceptibly altered. Removal of cofactor had no detectable impact on the extent of phosphorylation but thermal inactivation of the enzyme increased and mild reduction with sodium borohydride decreased the phosphorylatability of the aminotransferase. It was possible to separate the enzyme into phospho and dephospho forms by the use of DEAE chromatography. Validation that the two fractions represented genuine aminotransferase was obtained by proteolytic peptide mapping. The phospho form of the enzyme was found to possess little or no aminotransferase activity while that of the dephospho form exhibited higher specific activity than the purified enzyme prior to phosphorylation. Furthermore, the dephospho form of the enzyme could not be detectably phosphorylated by reincubation with the kinase following DEAE chromatography unless it was subjected to thermal inactivation. The stoichiometry of phosphorylation of the fraction containing 32P from DEAE chromatography was approximately 1 mole/mole of dimer. These results suggest that the substrate for phosphorylation by the kinase is a form of the aminotransferase which is somehow inactivated during routine purification even when extensive precautions are taken to maximally preserve catalytic activity.
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PMID:In vitro phosphorylation of 4-aminobutyrate aminotransferase by cAMP dependent protein kinase. 370 Jul 75

The mechanism of inactivation of pig brain gamma-aminobutyric acid aminotransferase (GABA-T) by (S)-4-amino-5-fluoropentanoic acid (1, R = CH2CH2COOH, X = F) previously proposed [Silverman, R. B., & Levy, M. A. (1981) Biochemistry 20, 1197-1203] is revised. apo-GABA-T is reconstituted with [4-3H]pyridoxal 5'-phosphate and inactivated with 1 (R = CH2CH2COOH, X = F). Treatment of inactivated enzyme with base followed by acid denaturation leads to the complete release of radioactivity as 6-[2-hydroxy-3-methyl-6-(phosphonoxymethyl)-4-pyridinyl]-4-oxo-5-+ ++hexenoic acid (4, R = CH2CH2COOH). Alkaline phosphatase treatment of this compound produces dephosphorylated 4 (R = CH2CH2COOH). These results support a mechanism that was suggested by Metzler and co-workers [Likos, J. J., Ueno, H., Feldhaus, R. W., & Metzler, D. E. (1982) Biochemistry 21, 4377-4386] for the inactivation of glutamate decarboxylase by serine O-sulfate (Scheme I, pathway b, R = COOH, X = OSO3-).
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PMID:Mechanism of inactivation of gamma-aminobutyrate aminotransferase by 4-amino-5-fluoropentanoic acid. First example of an enamine mechanism for a gamma-amino acid with a partition ratio of 0. 380 94

The binding site of Pyridoxal-5-P in 4-aminobutyrate aminotransferase was studied by using analogs of the cofactor. A phosphorothioate analog (PLP(S] recognizes the catalytic site; it forms a stable complex with the apoenzyme (KD = 1nM) and serves as cofactor during catalysis. Replacement of a non-bridged oxygen by sulfur in the phosphate side chain renders a compound which preserves the negative charges needed for correct alignment of the cofactor at the catalytic site. This phosphorothioate analog of PLP can be used to investigate the catalytic site of vitamin B6 dependent enzymes by means of 31P NMR spectroscopy. A bulky P-pyridoxamine derivative, ie, N-4-azido-2-nitrophenyl pyridoxyl-5-P (NANP) competes with natural cofactor for its binding site. Upon illumination, the arylazide of P-pyridoxamine acts as an efficient photolabeling reagent of the protein. A characteristic feature of this photolabeling reagent, ie, its ability to recognize the cofactor binding site, can be exploited to ascertain the chemical nature of amino acid residues at the catalytic site.
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PMID:Binding of new PLP analogs to the catalytic domain of GABA transaminase. 383 74


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