Disease relevance of Abat

• However, the sequence of AGT2 exhibited 30.8, 29.2, and 27.1% identity with those of Escherichia coli 4-aminobutyrate aminotransferase, rat ornithine aminotransferase, and Pseudomonas cepacia 2,2-dialkylglycine decarboxylase, respectively [1].
• After sustained epileptic seizures, the markedly increased expression of glutamate decarboxylase and the reduced expression of GABA transaminase may result in increased cytoplasmic GABA concentrations in granule cells [2].
• Identification of a familial mutation associated with GABA-transaminase deficiency disease [3].
• In comatose rats, a delayed disappearance of [3H]GABA was parallelled by a lower amount of metabolites, indirectly indicating a peripheral decrease of GABA-transaminase activity [4].
• The finding that glutamic acid decarboxylase activity in brain was reduced, together with the indirect evidence of a reduction in GABA-transaminase, may account for the steady state of GABA in hepatic encephalopathy [4].

Psychiatry related information on Abat

• Neonatal administration of a GABA-T inhibitor alters central GABAA receptor mechanisms and alcohol drinking in adult rats [5].
• Time-response studies on inhibition of GABA-T in whole brain demonstrated that at a dose of PLZ of 15 mg/kg i.p. inhibition of GABA-T remained relatively constant from 1 to 8 hr and that the enzyme was still inhibited by 23% at 24 hr after PLZ administration [6].
• The GABA transaminase inhibitor gamma-acetylene GABA reduced exploratory behaviors at doses much lower than those needed to reduce receptivity [7].
• It has previously been shown that chronic treatment with the GABA-transaminase inhibitor ethanolamine-O-sulphate (EOS), which elevates brain GABA levels by around 200%, selectivity enhances novel food consumption in rats treated with chlordiazepoxide (CDP) and given a food preference test [8].
• Together, these data suggest that GVG may be useful for the treatment of nicotine addiction and further support the strategy of targeting the GABAergic system with a suicide inhibitor of GABA-transaminase for the treatment of drug addiction [9].

High impact information on Abat

• Seizure protection and increased nerve-terminal GABA: delayed effects of GABA transaminase inhibition [10].
• SR 95103 (100 microM) did not interact with a variety of central receptors--in particular the GABAB, the strychnine, and the glutamate receptors--did not inhibit Na+-dependent synaptosomal GABA uptake, and did not affect GABA-transaminase and glutamic acid decarboxylase activities [11].
• Epileptic patients experienced an irreversible loss of their peripheral visual field upon treatment with vigabatrin (gamma-vinyl GABA), an inhibitor of the GABA degrading enzyme, GABA transaminase [12].
• Vigabatrin, the GABA-transaminase inhibitor, damages cone photoreceptors in rats [12].
• The actions of muscimol were probably mediated by its GABA agonist properties, since microinjection of an irreversible inhibitor of GABA transaminase (gamma-vinyl GABA) into the area of the SN also suppressed kindled seizures [13].

Chemical compound and disease context of Abat

• The concentration of gamma-aminobutyrate (GABA) and the activity of glutamate decarboxylase and GABA-transaminase were measured in extracts of mouse brain before the onset and during the course of generalized seizures induced by systemic administration of homocysteine thiolactone [14].
• 1. The GABA transaminase inhibitor and activator of glutamic acid decarboxylase, valproic acid is being used for the treatment of migraine [15].
• We found that homocarnosine produces dyskinesia similar to that observed with GABA antagonists and GABA-T inhibitors when applied directly to the cortex [16].
• There was no connection between ethanol intake, water intake, or body weight and GABA-T activity in any of the brain regions examined [17].
• To determine the generality of these findings we tested the ability of the GABA-T inhibitor ethanolamine-O-sulfate (EOS), to produce anorexia in three animal models of obesity: rats with medial hypothalamic lesions, rats exposed to palatable foods or Zucker fatty rats [18].

Biological context of Abat

• The amino acid sequence predicted from a rat liver cDNA library indicated that the precursor of beta-AlaAT I (4-aminobutyrate aminotransferase, beta-alanine-oxoglutarate aminotransferase) consists of a mature enzyme of 466 amino acid residues and a 34-amino acid terminal segment, with amino acids attributed to the leader peptide [19].
• About species specificity of brain 4-aminobutyrate-2-ketoglutarate transaminase (GABAT) [20].
• In vitro studies showed that the compound can inhibit GABA-T after hydrolysis by CNS esterases and that it enhanced GABAergic inhibition when applied to rat hippocampus slices [21].
• To evaluate the effects of the gamma-aminobutyric acid (GABA)ergic system on PRL secretion during sexual development in female rats, aminooxyacetic acid (an inhibitor of GABA-transaminase which increases the hypothalamic GABA concentration) was administered to 12- to 16- and 30-day-old female rats [22].
• Intracerebroventricular injections of gamma-aminobutyric acid (GABA) and of the GABA-transaminase inhibitor, ethanolamine-O-sulphate (EOS), decreased the food intake of freely-fed (GABA and EOS) and food-deprived rats (EOS) [23].

Anatomical context of Abat

• We have also detected GABA-T mRNA in GABAergic cells of rat cerebellar cortex by in situ hybridization [24].
• Our rat brain GABA-T cDNAs hybridize to mRNAs in brain and peripheral tissues, including liver, kidney, and testis [24].
• High doses of di-N-propylacetic acid only partially correct the GABA deficiency in the striatum, whereas low doses of gamma-acetylenic GABA, a specific irreversible inhibitor of GABA-T, completely restore the levels of GABA in striatum and substantia nigra [25].
• GABAergic innervation in cerebral blood vessels: an immunohistochemical demonstration of L-glutamic acid decarboxylase and GABA transaminase [26].
• The presence of GABAergic innervation in cerebral arteries of several species was investigated by an immunohistochemical method using antibodies against glutamic acid decarboxylase (GAD) and GABA transaminase (GABA-T) [26].

Associations of Abat with chemical compounds

• Inhibitory effect of ethanol administration on beta-alanine-2-oxoglutarate aminotransferase (GABA aminotransferase) in disulfiram-pretreated rats [27].
• Ethanol in the presence of disulfiram (N,N,N',N'-tetraethylthiuram disulfide, an inhibitor of aldehyde dehydrogenase) inhibited liver beta-alanine-oxoglutarate aminotransferase (beta-AlaAT I) activity yet activated tyrosine aminotransferase (TAT) in weanling rats in vivo [27].
• A rat brain cDNA encodes enzymatically active GABA transaminase and provides a molecular probe for GABA-catabolizing cells [24].
• The addition of beta-alanine to the diet significantly activated beta-AlaAT I in the kidneys of rats in accordance with changes in its mRNA level [28].
• In an attempt to improve this type of approach for measuring GABA turnover, the time course of GABA-T inhibition and accumulation of GABA in 12 regions of rat brain has been studied after systemic administration of aminooxyacetic acid (AOAA), injected at various doses and with different routes of administration [29].

Regulatory relationships of Abat

• Degradation of GABA by GABA-transaminase (GABA-T) was blocked by gamma-vinyl-GABA (GVG) and synthesis of GABA through glutamate decarboxylase (GAD) was suppressed with 3-mercaptopropionic acid (MPA) [30].
• In the globus pallidus, many pallidal neurons also displayed GABA-T immunoreactivity and many of the immunoreactive neurons were seen to express parvalbumin immunoreactivity [31].

Other interactions of Abat

• Our rat brain GABA-T probe hybridizes to Purkinje, basket, stellate, and Golgi II cells, the same GABAergic neurons previously shown to contain glutamate decarboxylase GAD65 and GAD67 [24].
• Neither beta-AlaAT I nor beta-AlaAT II activities in the kidney were affected by a high-protein diet [28].
• A tiny portion (around 15%) of reticulata neurons that display NMDAR1 immunoreactivity was found to be PV- or GABA-transaminase-negative [32].
• Age-related decreases were seen in choline acetyltransferase, acetylcholinesterase and 3H-QNB binding in some but not all brain regions, while GABA transaminase and MAO showed age-related increases [33].
• The activities of the two GABA shunt enzymes, glutamate dehydrogenase and GABA-transaminase, and of the NAD+-linked isocitrate dehydrogenase (ICDH) were inhibited whereas the glutamic acid decarboxylase, mitochondrial NADP+-linked ICDH, and succinic dehydrogenase activities remained unaltered in brain [34].

Analytical, diagnostic and therapeutic context of Abat

• cDNAs encoding gamma-aminobutyric acid aminotransferase (GABA-T) were isolated from a lambda ZAP rat hippocampal cDNA expression library by two independent cloning methods, immunological screening with an antimouse GABA-T antibody and plaque hybridization with a GABA-T cDNA probe derived by polymerase chain reaction [24].
• However, the mass of beta-AlaAT I from rat brain was larger than that from rat liver and kidney, as assessed by Western-blot analysis, mass spectroscopy and N-terminal sequencing [19].
• However, the beta-AlaAT I activity in the kidney was increased by protein-free and low-protein diets in relation to changes in its mRNA level [28].
• Since correction of the deficiency in gamma-aminobutyric acid (GABA) in HD may be of therapeutic value, the efficacy of drugs that inhibit the GABA-degrading enzyme (GABA-T) in elevating the levels of GABA has been examined in the animal model for HD [25].
• A total and rapidly occurring inhibition of GABA-T in all regions was obtained with intraperitoneal injection of 100 mg/kg AOAA, whereas after lower doses, marked regional differences in the degree of GABA-T inhibition were found, thus leading to underestimation of GABA synthesis rates, e.g., in substantia nigra [29].

References