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)

We report here the first purification to homogeneity of 4-aminobutyrate: 2-oxoglutarate aminotransferase (EC 2.6.1.19) (GABA-T) from an invertebrate source (locust) and its initial comparison with that of GABA-T from mammalian brain (sheep). The enzyme from both organisms was found to be a dimer of similar-sized subunits, with a native Mr of approx. 97,000. The pI of GABA-T from the locust was 6.7 and that of the sheep enzyme was 5.5. Michaelis constants for 4-aminobutyric acid (GABA) and 2-oxoglutarate were respectively 0.79 +/- 0.16 mM and 0.27 +/- 0.08 mM for the locust enzyme and 2.2 +/- 0.24 mM and 0.22 +/- 0.11 mM for the sheep enzyme. 5-(Aminomethyl)-3-isoxazolol (muscimol) was a competitive inhibitor of both enzymes, whereas 5-amino-1,3-cyclohexadienylcarboxylic acid (gabaculine) acted as a potent suicide substrate. However, 3-aminopropane-1-sulphonic acid, diaminobutyric acid, 1,2,3,4-tetrahydro-1-methyl-3-pyridinecarboxylic acid (isoguvacine), beta-(aminomethyl)-4-chlorobenzenepropanoic acid (baclofen), bicuculline and picrotoxin did not inhibit either enzyme at concentrations below 100 mM. Polyclonal antisera raised against GABA-T from the sheep failed to cross-react with the enzyme from locust in either an Ouchterlony immunodiffusion plate or a competitive enzyme-linked immunosorbent assay. The purification procedures differed considerably. Ion-exchange chromatography, which was found suitable for the purification of GABA-T from the sheep, was ineffective with locust enzyme, which was finally purified by hydrophobic-interaction chromatography and chromatofocusing.
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PMID:Purification and partial characterization of 4-aminobutyrate:2-oxoglutarate aminotransferase from sheep brain and locust ganglia. 335 98

Hepatic coma was induced in rats chronically treated with CCl4, by means of a single injection of ammonium acetate. The activities of glutamate decarboxylase (GAD) and GABA transaminase (GABA-T), as well as the synaptosomal uptake and release of [3H]GABA, were measured in the following brain areas of the comatose rats: cortex, striatum, hypothalamus, hippocampus, midbrain and cerebellum. Hepatic coma was associated with a general decrease of GAD activity, whereas GABA-T activity was diminished only in the hypothalamus, striatum and midbrain. During hepatic coma, the K+-stimulated [3H]GABA release was notably diminished in the striatum and cerebellum, whereas a significant increase was observed in the hippocampus. [3H]GABA uptake increased in most regions after CCl4 treatment, independently of the presence of coma. The results indicate that GABAergic transmission seems to be decreased in most cerebral regions during hepatic coma.
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PMID:Regional brain GABA metabolism and release during hepatic coma produced in rats chronically treated with carbon tetrachloride. 336 28

Suppression of kindled amygdala seizures in rats followed bilateral infusion of the GABA transaminase inhibitor gamma-vinyl-GABA (GVG) into the endopiriform area of the forebrain. The deep prepiriform cortex of the rat is an important site for both initiation and arrest of generalized seizures induced by systemic convulsants. To determine whether this area also regulates the spread of amygdala seizures, the irreversible GABA-transaminase blocking agent, GVG (vigabatrin) was infused bilaterally in the deep prepiriform area in amygdala-kindled rats. Twenty-four hours after the infusion, kindled seizure threshold was elevated in 12 of 13 rats tested. If homologous areas exist in the primate brain, treatment strategies that take advantage of critical areas for seizure spread by local infusion of inhibitory agents or transplantation of GABA-containing cells may be developed for suppressing intractable seizures in humans.
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PMID:gamma-Vinyl GABA in endopiriform area suppresses kindled amygdala seizures. 339 Nov 46

Serum concentrations of gamma-aminobutyric acid (GABA) are increased in liver failure, possibly because of decreased hepatic GABA catabolism. To study in detail the role of the liver in GABA metabolism, uptake and catabolism of GABA by isolated perfused liver from normal rats and rats with galactosamine- or carbon tetrachloride-induced liver failure were measured. Hepatic GABA uptake was almost complete at GABA concentrations of up to 10 microM and approached saturation at a concentration of 50 microM. The apparent affinity of hepatic GABA uptake was 38 microM and the apparent maximal velocity was 158 nmol/g.min. Hepatic GABA uptake was sodium-dependent. gamma-Aminobutyric acid taken up by the liver was rapidly catabolized as measured by 14CO2 formation from [U-14C]GABA. Aminooxyacetic acid, a GABA transaminase inhibitor, completely and irreversibly inhibited hepatic GABA catabolism and thereby also inhibited hepatic GABA uptake. Although uptake of GABA by livers of carbon tetrachloride- or galactosamine-treated rats was decreased (apparent maximal velocity, 103 and 98 nmol/g.min, respectively), at physiologic GABA concentrations in the perfusate GABA uptake and catabolism was not different from that of untreated controls. The observed impairment of hepatic GABA uptake or catabolism by the diseased liver would be expected to contribute to increased GABA levels in peripheral blood plasma in liver failure. However, the magnitude of the observed impairment would be insufficient to account for a 10-fold increase in such levels.
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PMID:Uptake and catabolism of gamma-aminobutyric acid by the isolated perfused rat liver. 339 67

1. Oral administration of the GABA transaminase inhibitor ethanolamine-O-sulphate (EOS, 5 mg/ml in drinking water) to rats for 14 days suppressed food intake by 24%, but reduced weight gain by over 35%. 2. Thus, feed efficiency (g gain/MJ eaten) was decreased by over 15% in EOS-treated rats, suggesting that there had been an increase in metabolic rate. 3. The thermogenic response (rise in oxygen consumption, VO2) to injection of noradrenaline was enhanced by 50% and the thermogenic activity of brown adipose tissue (BAT, assessed from mitochondrial GDP-binding) was increased by 38% in EOS-treated rats. 4. Injection of baclofen (a GABAB agonist, 0.5 mg/kg s.c.) stimulated VO2 in both groups, with a significantly greater response in EOS treated rats, and this was enhanced by bicuculline (GABAA antagonist, 0.5 g/kg s.c.) in control rats and attenuated by muscimol (GABAA agonist, 0.5 mg/kg s.c.) in control and EOS-treated rats. 5. The data indicate that increasing brain GABA concentrations with EOS results in lower levels of metabolic efficiency and increases in thermogenesis.
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PMID:Chronic inhibition of GABA transaminase results in activation of thermogenesis and brown fat in the rat. 341 1

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

3-Nitro-1-propanamine is a close structural analog of the neuro-transmitter GABA. The nitro compound is a good substrate for the GABA aminotransferase from porcine brain. However, it inactivates the GABA aminotransferase from GABA-grown Pseudomonas fluorescens in a slowly reversible reaction. Both enzymes are inactivated by the homolog 4-nitro-1-butanamine.
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PMID:Inactivation of GABA aminotransferase by 3-nitro-1-propanamine. 350 12

Different methods for measuring GABA turnover in rat brain were compared. One method was based on the irreversible inhibition of GABA transaminase (EC 2.6.1.19) by microinjection of gamma-vinyl-GABA into neostriatum of rat. The accumulation of GABA was almost linear for 4 hr. The GABA turnover in control animals was estimated to be 25.8 +/- 1.1 nmole/mg protein/hr. Another method was based on the post mortal increase in GABA level in an 8 min interval after decapitation. This method gave a GABA turnover of 54.3 +/- 4.8 nmole/mg protein/hr in neostriatum. The methods were compared with respect to their ability to detect the effect of high doses of diazepam and morphine on the turnover rate of GABA. The GABA transaminase inhibition method resulted in a 27% and a 17% decrease in GABA turnover for diazepam and morphine respectively. The post mortem method did not detect any change in GABA turnover after administration of these drugs. Hypoglycemia leads to a decrease in GABA turnover of 17% with the GABA transaminase inhibition method and a 43% decrease in GABA turnover with the post mortem method. The advantages and limitations of the methods for estimating GABA turnover changes during drug exposure is discussed, and are compared with results from a third method based on steady state kinetics extracted from the literature.
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PMID:Comparison of results obtained with different methods for estimating GABA turnover in rat neostriatum. 355 8

Vigabatrin (gamma-vinyl GABA), an enzyme-activated, irreversible inhibitor of GABA transaminase, was administered orally to albino Sprague Dawley and pigmented Lister-Hooded rats. A dose-dependent retinal lesion characterized histologically by disruption of the outer nuclear layer was observed in the Sprague Dawley rat but not in Lister-Hooded rats, indicating that this alteration is related to the absence of pigment. The lesion is similar to that induced in albino rats by light and certain drugs. In addition, myelin vacuolation of the brain was observed in both rat strains, consistent with the findings of other toxicity studies with vigabatrin. In all cases, the vacuolation was limited to myelinated tracts and resulted from separation of the myelin sheath at the intraperiod line. There was no evidence of demyelination, axonal degeneration or damage to contiguous structures in the affected areas. The vacuolation is histologically similar to that induced in rats by certain other compounds such as isoniazid, hexachlorophene, and triethyltin, but differs in that it is focal in distribution, it is limited to the brain, and is reversible upon cessation of treatment.
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PMID:A study of the effects of vigabatrin on the central nervous system and retina of Sprague Dawley and Lister-Hooded rats. 361 99

The turnover of GABA (estimated from the post-mortem accumulation of GABA), and the activity of glutamic acid decarboxylase and GABA transaminase, along with the saturation of both enzymes by cofactor pyridoxal phosphate, were studied in the substantia nigra of rats of both sexes. Although no sex differences were found in the in vitro measured characteristics of both enzymes involved in GABA metabolism, the turnover of GABA was greater in males. This finding is consistent with our previous reports showing the greater resistance of male rats to GABA-related convulsions.
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PMID:Sex difference in the turnover of GABA in the rat substantia nigra. 368 Dec 88


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