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PubMed1995

Identification of a mitochondrial form of kynurenine aminotransferase/glutamine transaminase K from rat brain.

A soluble aminotransferase with kynurenine aminotransferase (KAT) activity has been recently isolated from rat brain. This enzyme corresponds to a cytosolic form of glutamine transaminase K (GTK). In addition to the cytosolic enzyme, a mitochondrial-associated form of this KAT/GTK also exists. In the present work we have isolated a rat brain cDNA clone encoding a KAT/GTK enzyme identical to the soluble form but carrying an additional stretch of 32 amino acids at its NH2-terminus. Several structural features of this sequence resemble those of leader peptides for mitochondrial import. Evidence that the isolated cDNA encoded for mitochondrial KAT/GTK was obtained after transfection of HEK-293 cells with the cDNA coding for this new KAT/GTK isoenzyme. In fact, a significant enrichment of both KAT and GTK enzymatic activities was found in the crude mitochondrial fraction of the transfected cells.

Amino Acid Sequence↗
PubMed1990

Crystallization and preliminary X-ray analysis of gamma-aminobutyric acid transaminase.

gamma-Aminobutyric acid transaminase from pig liver, an alpha 2 dimeric enzyme of Mr 110,100, has been crystallized by the vapour diffusion method with polyethylene glycol as precipitant. The crystals are monoclinic, space group P2(1), unit cell dimensions a = 82.1 A, b = 230.0 A, c = 70.3 A, beta = 123.9 degrees and diffract to 2.5 A resolution. There are two dimers per asymmetric unit.

4-Aminobutyrate Transaminase↗
PubMed1988

GABA transaminase inhibitors enhance the release of endogenous GABA but decrease the release of beta-alanine evoked by electrical stimulation of slices of the rat medulla oblongata.

Slices of the rat medulla oblongata were superfused and electrically stimulated. The amount of endogenous GABA, beta-alanine and glutamate release from the slices was determined by high performance liquid chromatography with fluorometric detection. Inhibitors of GABA-transaminase (GABA-T), aminooxyacetic acid (10(-5) M), gamma-acetylenic GABA (10(-4) and 10(-3) M) and gabaculine (10(-5) M), enhanced the stimulus-evoked release of GABA and reduced that of beta-alanine, while no change was observed in the release of glutamate. These changes in amino acid release from the slices were accompanied by an increase in the content of GABA and a decrease in that of beta-alanine. The stimulus-evoked release of these amino acids was abolished by Ca2+-deprivation, in either the presence or absence of GABA-T inhibitors. These results suggest a modulatory role of GABA-T for synaptically releasable GABA and involvement of this enzyme in the synthesis of releasable beta-alanine.

4-Aminobutyrate Transaminase↗
PubMed1982

Does homocarnosine mediate the dyskinetic movements induced by gaba-transaminase inhibitors.

Unilateral application of gamma-aminobutyric acid (GABA) antagonists on the motor cortex of conscious rats produces myoclonic movements. Paradoxically, the same behaviour can be observed with high concentrations of some GABA-transaminase (GABA-T) inhibitors. Since the GABA conjugate homocarnosine is increased in the brain following GABA-T inhibition and since homocarnosine is known to displace [3H]-GABA from its binding sites at high concentration, we investigated whether homocarnosine might explain the dyskinetic movements produced by these GABA-T inhibitors. We found that homocarnosine produces dyskinesia similar to that observed with GABA antagonists and GABA-T inhibitors when applied directly to the cortex. However, this property of homocarnosine is unlikely to be the basis of the dyskinetic effect of GABA-T inhibitors since we found no relationship between brain homocarnosine levels and the appearance of abnormal movements following GABA-T inhibition.

4-Aminobutyrate Transaminase↗
PubMed1986

Differential effect of gamma-vinyl GABA and valproate on GABA-transaminase from cultured neurones and astrocytes.

A preferential effect of valproate on gamma-aminobutyric acid (GABA) in the nerve terminal compartment has been proposed. Gamma-vinyl GABA, an irreversible inhibitor of GABA-transaminase (GABA-T) causes a preferential increase in the GABA compartment of the non-nerve terminal. The aim of the present study was to investigate further this apparent differential effect on GABA-T of these compounds in neurones and glia. The investigations were undertaken in neurones and astrocytes, cultured separately. After incubation with valproate, the IC50 value for astrocytes was found to be 1202 microM of valproate and for neurones 634 microM. Assuming regional differences of concentrations of valproate in the brain, the observed IC50 values might be clinically relevant. Culturing the cells in the presence of gamma-vinyl GABA demonstrated IC50 values for astrocytes and neurones of 89 and 24 microM, respectively. The (S)isomer of gamma-vinyl GABA was the most active inhibitor of GABA-T in both glia and neurones. After withdrawal of gamma-vinyl GABA from the culture media of the cells, in neurones 50% of the activity of GABA-T was regained within 2-4 days. In astrocytes a similar time course was observed. These findings are in agreement with clinical data: the IC50 values correspond to clinically-relevant serum levels of gamma-vinyl GABA in humans only the (S)isomer showed an antiepileptic effect in animal models of epilepsy a delayed antiepileptic effect, after withdrawal of gamma-vinyl GABA, has been established in clinical studies.

4-Aminobutyrate Transaminase↗
PubMed1994

Anxiolytic-like effect of the GABA-transaminase inhibitor vigabatrin (gamma-vinyl GABA) on rat exploratory activity.

Vigabatrin (gamma-vinyl GABA, GVG) is an irreversible inhibitor of GABA-transaminase (GABA-T). This study addressed the question of whether or not the inhibition of GABA-T has an anxiolytic effect in rats. Diazepam (1.5 mg/kg) and GVG (50 and 500 mg/kg) increased the tendency of rats to explore in the elevated plus-maze test, whereas the effect of general locomotor activity was diminished. The sedative effect of GVG (500 mg/kg) was more pronounced 6 h than 2 h after IP administration. The present findings suggest that even a partial inhibition of GABA-T results in a reduction of anxiety measures in a novel environment.

4-Aminobutyrate Transaminase↗
PubMed1993

Electromyographic activity of rat ischiocavernosus muscles during copulation after treatment with a GABA-transaminase inhibitor.

The administration of GABA-transaminase inhibitors (GABA-TIs) to male rats reduces the proportion of mounts that result in intromissions. Copulatory pelvic thrusting remains normal, despite the fact that animals treated with GABA-TIs show gross deficiencies in other motor acts. In order to determine whether altered sexual behavior produced by GABA-TI could be due to deficiencies in activity of striated penile muscles, we recorded the electromyographic (EMG) activity of the ischiocavernosus (IC) muscle during copulation in male rats treated with sodium valproate. The duration of IC EMG bursts was reduced by sodium valproate in separate tests that allowed or prevented intromission. There was no effect on EMG amplitude or frequency. It is suggested that insufficient activity of the IC muscles reduces the likelihood of vaginal penetration. The actions of GABA may be localized to hypothalamic or brain stem nuclei with GABAergic projections to the spinal motoneurons controlling the IC muscles, or GABA may act directly on these neurons.

4-Aminobutyrate Transaminase↗
PubMed1985

Effect of selective parasympathetic denervation on the daily rhythm of tyrosine transaminase in the rat liver.

The effect of section of the rostral hepatic nerve (RNH), branch of the left abdominal vagus, on the circadian rhythm of tyrosine transaminase (TAT) activity in rat liver has been investigated. It has been shown that the midnight peak of TAT activity is suppressed after section of the rostral hepatic nerve and by subdiaphragmatic vagotomy, but is unaffected by sham-operation and section of the ventral abdominal vagus caudal to the emergence of the rostral hepatic nerve. It is concluded that the rhythm of TAT activity is under neural control, either directly or reflexely.

Animals↗
PubMed1994

Effects of chronic treatment with the GABA-transaminase inhibitor vigabatrin on exploratory behaviour in rats.

Vigabatrin (gamma-vinyl GABA, GVG) is an irreversible inhibitor of the enzyme GABA-transaminase (GABA-T) GABA-T is the enzyme responsible for the catabolism of the major inhibitory neurotransmitter gamma-aminobutyric acid (GABA) in the mammalian brain. Previously, a single administration of vigabatrin at a dose of 50 mg/kg was found to produce an anxiolytic-like effect on exploratory behaviour in rats and a decrease in the locomotor activity, 2 and 4 h after the injection and, presently, 24 h after the injection. Using an elevated plus-maze and open field tests, we investigated whether or not chronic administration of vigabatrin at the same dose (50 mg/kg/day, i.p.) for 14 and 28 days induces tolerance with regard to these effects. The anxiolytic-like effect of vigabatrin was found to persist in the elevated plus-maze test, as was the case with diazepam (5 mg/kg/day, i.p.), 24 h after the last injection. However, in the plus-maze and open field tests, the effects of vigabatrin and diazepam on the general locomotor activity were not found to be decreased.

4-Aminobutyrate Transaminase↗
PubMed1995

Effect of the GABA-transaminase inhibitor vigabatrin on exploratory behaviour in socially isolated rats.

Elevation of the brain levels of the major inhibitory neurotransmitter gamma-aminobutyric acid (GABA) by inhibiting the GABA-catabolizing enzyme GABA-transaminase (GABA-T) is known to induce a number of functional effects including changes in behaviour. Vigabatrin (gamma-vinyl GABA, GVG) is an anti-epileptic drug that increases brain GABA levels by an irreversible inhibition of GABA-T. Using the elevated plus-maze model of anxiety and the open-field behaviour test, the effects of GABA-T inhibition and social isolation on rat exploratory behaviour were investigated. Social isolation for 1 week did not induce any change in the exploratory-behaviour of adult rats. However, rats socially isolated for 2 weeks, showed suppressed exploratory behaviour in the elevated plus-maze test. In both groups of differentially housed rats, treatment with vigabatrin at a dose of 250 mg/kg, i.p., significantly reduced the anxiety level in the plus-maze test. In the open-field test, vigabatrin tended to increase the exploratory behaviour only in the group of isolated rats. The results may suggest that vigabatrin has a better anxiolytic-like effect in the isolated rats than that in the socially housed rats.

4-Aminobutyrate Transaminase↗
PubMed1992

Detritiation of L-[3-3H]alanine in the glutamate-pyruvate transaminase reaction.

The detritiation of L-[3-3H]alanine in the reaction catalyzed by pig heart glutamate-pyruvate transaminase was monitored in the absence or presence of lactate dehydrogenase. The results indicated that each monodirectional conversion of L-[3-3H]alanine to [3-3H]pyruvate resulted in the generation of 3HOH at a rate representing one-third of the total 3H flux. No isotopic discrimination in reaction velocity between tritiated and 14C-labelled L-alanine was observed. The mathematical modelling of the reaction revealed that, as a consequence of the detritiation process, the steady-state ratio in L-[3-3H]alanine/[3-3H]pyruvate does not inform on either the absolute or relative size of the amino acid and 2-keto acid pools.

Alanine↗
PubMed1986

Murine acetaminophen hepatotoxicity: temporal interanimal variability in plasma glutamic-pyruvic transaminase profiles and relation to in vivo chemical covalent binding.

The hepatotoxicity of acetaminophen is thought to be dependent upon its enzymatic bioactivation to a reactive intermediary metabolite which binds covalently to essential cellular macromolecules, thereby causing cellular death. Traditional in vivo methods using smaller mammals are mechanistically restrictive in that measures of hepatotoxicity, such as plasma glutamic-pyruvic transaminase (GPT), and chemical covalent binding to hepatocellular protein are performed at different times in separate groups of animals. We developed a microanalytical technique which allowed repetitive plasma GPT sampling from individual mice, followed by delayed determination of covalent binding in the same mouse 36 hr after acetaminophen administration. Diethyl ether anesthesia was used to enhance acetaminophen hepatotoxicity. The repetitive sampling technique permitted an accurate determination of the peak GPT concentration, which exhibited a marked interanimal variability in the time of occurrence. Individual peak GPT concentrations correlated with the respective covalent binding of acetaminophen in each mouse (r = 0.82, p less than 0.05), while the traditional method using a fixed sampling time (24 hr) failed to correlate (r = 0.50, p greater than 0.05). Ether produced a 39-fold enhancement in the severity of acetaminophen hepatotoxicity; however, a single, fixed-time sample taken at either 12 or 24 hr produced a substantial and inconsistent over- or underestimate of this toxicologic enhancement. This study shows that chemical hepatotoxicity as reflected by plasma GPT concentration cannot be quantified accurately by a single blood sample obtained from a given animal, regardless of the chosen sampling time.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetaminophen↗
PubMed1983

GABA and feeding: reversal of overeating by central GABA-transaminase inhibition.

Past literature is reviewed briefly which suggests that variations in brain GABA metabolism may be involved in the control of food intake in rats. Recent experiments from the author's laboratory are summarized in which brain GABA has been elevated in adult female rats by intracisternal injection of the GABA-transaminase inhibitor, ethanolamine-O-sulfate (EOS). Central EOS pretreatment produced dose-dependent anorexia in normal subjects and prevented acute overeating in response to systemic insulin (12 U/kg) or 2-deoxyglucose (750 mg/kg). Similar EOS pretreatment essentially reversed the chronic overeating induced by diet palatability, bilateral medial hypothalamic lesions or genetic predisposition (in Zucker fatty rats). The ubiquity of these anorexic effects in the absence of clear motor debilitation suggests that drugs which elevate brain GABA deserve further investigation for their potential utility in the clinical treatment of overeating.

4-Aminobutyrate Transaminase↗
PubMed1994

A Lactobacillus nifS-like gene suppresses an Escherichia coli transaminase B mutation.

The nifS gene was first identified in nitrogen-fixing bacteria where its protein product is essential for efficient nitrogen fixation. Here, we demonstrate that a nifS-like gene also occurs in Lactobacillus bulgaricus, an organism which does not fix nitrogen, and that the nifS gene product suppresses the leucine auxotrophy of an ilvD, ilvE Escherichia coli strain. The known nifS genes from prokaryotes and eukaryotes exhibit a high degree of sequence conservation although the genes have diverse functions, as shown by their ability to complement or suppress dissimilar mutations. It was suggested that the nifS gene products represent a group of enzymes which mediate a specific chemical reaction common to diverse metabolic pathways. The purified NifS protein from Azotobacter vinelandii was experimentally shown to be a pyridoxal phosphate-dependent cysteine desulfurase. Curiously, the NifS proteins exhibit also a remarkable sequence homology to a new class of pyridoxal phoshate-dependent aminotransferases. We show that the L bulgaricus NifS-like protein is able to replace in vivo transaminase B in E coli. This experimental observation supports the prediction that some NifS-like proteins may be aminotransferases.

Amino Acid Sequence↗
PubMed1986

Specific, vascular localization of GABA-transaminase in the guinea pig lung.

The occurrence and distribution of 4-aminobutyrate:2-oxoglutarate transaminase (GABA-T) activity were examined in the guinea pig lung using biochemical and enzymehistochemical methods. Specific GABA-T reactivity was confined primarily to the arteries and to a lesser extent to the veins. No activity could be observed in association with bronchi, alveoli and nerve fibers. Our findings indicate that the GABA-T activity in the lung is specifically located in blood vessels. This study is the first to demonstrate GABA-T activity in peripheral blood vessels.

4-Aminobutyrate Transaminase↗
PubMed1986

The distribution of GABA-transaminase-dehydrogenase activity in the myenteric plexus of rat small intestine: a histochemical analysis.

The presence and distribution of gamma-aminobutyric acid (GABA) degradative enzyme (GABA transaminase-succinic semialdehyde dehydrogenase) activity in the rat myenteric plexus was determined histochemically using laminar preparations of the small intestine. Blue-diformazan staining resulting from reduction of the tetrazolium salt, Nitro-BT, during GABA catabolism was present in a scattered population of ileal and jejunal myenteric ganglion cells, including those resembling multipolar type II and unipolar nerve cells. Such staining was almost completely prevented under conditions of GABA-T inhibition. These results indicate that GABA is enzymically degraded at specific sites in the rat enteric nervous system where it is proposed to have a neurotransmitter function.

4-Aminobutyrate Transaminase↗
PubMed1990

L-Alanine: 4,5-dioxovalerate transaminase does not regulate heme synthesis in rat liver.

L-Alanine: 4,5-dioxovalerate transaminase (ADT) was determined in liver homogenates of rats treated by either inducers of porphyrin synthesis or the repressor, hemin. ADT activity was not induced by the porphyrinogenic agents nor reduced by hemin, indicating that ADT probably has no regulatory role in the heme synthesis pathway. The same conclusion was drawn from similar experiments performed in monolayers of chick embryo liver cells.

Alanine↗
PubMed1988

Chronic inhibition of GABA transaminase results in activation of thermogenesis and brown fat in the rat.

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.

4-Aminobutyrate Transaminase↗