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)

Dysfunctions of glutamatergic and GABAergic neurotransmission are two important hypotheses for the pathogenesis of schizophrenia. Thus, genes in the pathway are candidates for schizophrenia susceptibility. Phosphate-activated glutaminase (GLS), glutamine synthetase (GLUL), glutamic acid decarboxylase (GAD), GABA transaminase (ABAT) and succinic semialdehyde dehydrogenase (ALDH5A1) are five primary enzymes in glutamate and GABA synthetic and degradative pathway. In order to investigate the possible involvement of these genes in the development of paranoid schizophrenia, we genotyped 80 paranoid schizophrenics from northern China and 108 matched controls by polymerase chain reaction (PCR) and restriction fragment length polymorphisms (RFLP) methods or directly sequencing of PCR product. Seven SNPs were found to be polymorphic in the population investigated. No significant differences in the genotype distributions or allele frequencies between patients and controls were found. Therefore, we conclude the polymorphisms studied in the five genes do not play major roles in pathogenesis of paranoid schizophrenia in the population investigated.
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PMID:An association study between polymorphisms in five genes in glutamate and GABA pathway and paranoid schizophrenia. 1564 43

In the mammalian central nervous system (CNS), the inhibitory GABAergic system is composed of different signaling molecules such as glutamate decaroxylase, vesicular GABA transporters, GABA receptors, GABA transporters and GABA transaminase. A prevailing view is that the balance between excitatory signaling mediated by glutamate and inhibitory signaling mediated by GABA plays a pivotal role in mechanisms underlying the modulation and maintenance of a variety of neural functions. Therefore, abnormalities in a GABAergic signaling molecule would lead to a crisis of severe symptoms relevant to a number of neuropsychiatric disorders. These include epilepsy, depression, schizophrenia, stiff-person syndrome, drug addiction and so on. In this review article, we will summarize recent studies on the relationship between the malfunction of GABAergic signaling molecules and the etiology of these neuropsychiatric disorders. We will also refer to novel strategies on GABAergic signaling molecules other than GABA receptors for therapeutic usefulness in the future.
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PMID:[Neuropsychiatric disorders and GABA]. 1565 2

Enaminones are a novel group of compounds that have been shown to possess anticonvulsant activity in in vivo animal models of seizures. The cellular mechanism by which these compounds produce their anticonvulsant effects is not yet known. This study examined the effects of enaminones on excitatory synaptic transmission. We studied the effects of 3-(4'-chlorophenyl)aminocyclohex-2-enone (E118), methyl 4-(4'-bromophenyl)aminocyclohex-3-en-6-methyl-2-oxo-1-oate (E139) and ethyl 4-(4'-hydroxyphenyl)aminocyclohex-3-en-6-methyl-2-oxo-1-oate (E169) on isolated evoked, glutamate-mediated excitatory synaptic responses by recording whole-cell currents and potentials in cells of the nucleus accumbens (NAc) contained in forebrain slices. The anticonvulsant enaminones (E118 and E139), but not E169, depressed NMDA and non-NMDA receptor-mediated synaptic responses. The inhibition of the non-NMDA response was concentration-dependent (1.0-100 microM) with a maximal depression of approximately -30%. E118 and E139 had similar potencies (EC(50)=3.0 and 3.5 microM, respectively) in depressing this response but E139 was more efficacious (E(max)=-31.3+/-3.8%) than E118 (E(max)=-22.6+/-1.6%). The excitatory postsynaptic current (EPSC) depression caused by 10 microM E139 (-27.7+/-3.8%) was blocked by 1 microM CGP55845 (6.3+/-8.1%), a potent GABA(B) receptor antagonist. Pretreatment of slices with gamma-vinylGABA and 1-(2-(((diphenylmethylene)imino)oxy)ethyl)-1,2,5,6-tetrahydro-3-pyridine-carboxylic acid (NO-711), an irreversible GABA transaminase (GABA-T) inhibitor and a GABA reuptake blocker, respectively, like the anticonvulsant enaminones, also caused a depression of the evoked EPSC (-38.1+/-14.1 and -24.1+/-8.9%, respectively). In the presence of these compounds, E139 did not cause a further depression of the EPSC. Our data suggest that anticonvulsant enaminones cause EPSC depression by enhancing extracellular GABA levels possibly through the inhibition of either GABA reuptake or GABA-T enzyme, or both.
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PMID:Anticonvulsant enaminones depress excitatory synaptic transmission in the rat brain by enhancing extracellular GABA levels. 1591 38

Ornithine aminotransferase and 4-aminobutyrate aminotransferase are related pyridoxal phosphate-dependent enzymes having different substrate specificities. The atomic structures of these enzymes have shown (i) that active site differences are limited to the steric positions occupied by two tyrosine residues in ornithine aminotransferase and (ii) that, uniquely among related, structurally characterized aminotransferases, the conserved arginine that binds the alpha-carboxylate of alpha-amino acids interacts tightly with a glutamate residue. To determine the contribution of these residues to the specificities of the enzymes, we analyzed site-directed mutants of ornithine aminotransferase by rapid reaction kinetics, x-ray crystallography, and 13C NMR spectroscopy. Mutation of one tyrosine (Tyr-85) to isoleucine, as found in aminobutyrate aminotransferase, decreased the rate of the reaction of the enzyme with ornithine 1000-fold and increased that with 4-aminobutyrate 16-fold, indicating that Tyr-85 is a major determinant of specificity toward ornithine. Unexpectedly, the limiting rate of the second half of the reaction, conversion of ketoglutarate to glutamate, was greatly increased, although the kinetics of the reverse reaction were unaffected. A mutant in which the glutamate (Glu-235) that interacts with the conserved arginine was replaced by alanine retained its regiospecificity for the delta-amino group of ornithine, but the glutamate reaction was enhanced 650-fold, whereas only a 5-fold enhancement of the ketoglutarate reaction rate resulted. A model is proposed in which conversion of the enzyme to its pyridoxamine phosphate form disrupts the internal glutamate-arginine interaction, thus enabling ketoglutarate but not glutamate to be a good substrate.
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PMID:Determinants of substrate specificity in omega-aminotransferases. 1609 75

Recent studies have suggested that the globus pallidus may be a particularly sensitive target of manganese (Mn), however, in vitro studies of the effects of Mn on GABAergic neurons have been restricted by the lack of a cell model expressing GABAergic properties. Here, we investigated the effects of low-level Mn treatment on cellular GABA and glutamate metabolism using the newly characterized AF5 rat neural-derived cell line, which displays GABAergic properties during culture in vitro. Intracellular GABA and glutamate levels were measured along with measurement of the release of GABA and glutamate into the culture medium, glutamine uptake from the culture medium, and the specific effects of Mn on the enzymes directly responsible for the synthesis and degradation of GABA, glutamate decarboxylase (GAD) and GABA transaminase (GABA-T). Our results demonstrate that Mn had no effect on the activities of GAD or GABA-T. Similarly, low-level Mn treatment of AF5 cultures had only a small effect on intracellular GABA levels (114% of control) and no effect on the release of GABA. In contrast, intracellular and extracellular glutamate levels were enhanced to 170 and 198% of control during Mn treatment, respectively, while extracellular glutamine decreased to 73% of controls. Together, these results suggest that glutamate homeostasis may be preferentially affected over GABA in AF5 cells during low-level Mn treatment, suggesting a novel mechanism by which Mn-induced excitotoxicity might arise.
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PMID:Low-level manganese exposure alters glutamate metabolism in GABAergic AF5 cells. 1732 Jan 82

The vitamin B(6)-derived pyridoxal 5'-phosphate (PLP) is the cofactor of enzymes catalyzing a large variety of chemical reactions mainly involved in amino acid metabolism. These enzymes have been divided in five families and fold types on the basis of evolutionary relationships and protein structural organization. Almost 1.5% of all genes in prokaryotes code for PLP-dependent enzymes, whereas the percentage is substantially lower in eukaryotes. Although about 4% of enzyme-catalyzed reactions catalogued by the Enzyme Commission are PLP-dependent, only a few enzymes are targets of approved drugs and about twenty are recognised as potential targets for drugs or herbicides. PLP-dependent enzymes for which there are already commercially available drugs are DOPA decarboxylase (involved in the Parkinson disease), GABA aminotransferase (epilepsy), serine hydroxymethyltransferase (tumors and malaria), ornithine decarboxylase (African sleeping sickness and, potentially, tumors), alanine racemase (antibacterial agents), and human cytosolic branched-chain aminotransferase (pathological states associated to the GABA/glutamate equilibrium concentrations). Within each family or metabolic pathway, the enzymes for which drugs have been already approved for clinical use are discussed first, reporting the enzyme structure, the catalytic mechanism, the mechanism of enzyme inactivation or modulation by substrate-like or transition state-like drugs, and on-going research for increasing specificity and decreasing side-effects. Then, PLP-dependent enzymes that have been recently characterized and proposed as drug targets are reported. Finally, the relevance of recent genomic analysis of PLP-dependent enzymes for the selection of drug targets is discussed.
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PMID:Pyridoxal 5'-phosphate enzymes as targets for therapeutic agents. 1750 14

A large amount of gamma-aminobutyric acid (GABA) was found to accumulate in tomato (Solanum lycopersicum) fruits before the breaker stage. Shortly thereafter, GABA was rapidly catabolized after the breaker stage. We screened the GABA-rich tomato cultivar 'DG03-9' which did not show rapid GABA catabolism after the breaker stage. Although GABA hyperaccumulation and rapid catabolism in fruits is well known, the mechanisms are not clearly understood. In order to clarify these mechanisms, we performed comparative studies of 'Micro-Tom' and 'DG03-9' fruits for the analysis of gene expression levels, protein levels and enzymatic activity levels of GABA biosynthesis- and catabolism-related enzymes. During GABA accumulation, we found positive correlations among GABA contents and expression levels of SlGAD2 and SlGAD3. Both of these genes encode glutamate decarboxylase (GAD) which is a key enzyme of GABA biosynthesis. During GABA catabolism, we found a strong correlation between GABA contents and enzyme activity of alpha-ketoglutarate-dependent GABA transaminase (GABA-TK). The contents of glutamate and aspartate, which are synthesized from GABA and glutamate, respectively, increased with elevation of GABA-TK enzymatic activity. GABA-TK is the major GABA transaminase form in animals and appears to be a minor form in plants. In 'DG03-9' fruits, GAD enzymatic activity was prolonged until the ripening stage, and GABA-TK activity was significantly low. Taken together, our results suggest that GAD and GABA-TK play crucial roles in GABA accumulation and catabolism, respectively, in tomato fruits.
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PMID:Biochemical mechanism on GABA accumulation during fruit development in tomato. 1871 63

Pea plants incubated in 15N2 rapidly accumulated labeled gamma-aminobutyrate (GABA) in the plant cytosol and in bacteroids of Rhizobium leguminosarum bv. viciae 3841. Two pathways of GABA metabolism were identified in R. leguminosarum 3841. In the first, glutamate is formed by GABA aminotransferase (GabT), transferring the amino group from GABA to 2-oxoglutarate. In the second, alanine is formed by two omega-aminotransferases (OpaA and OpaB), transferring the amino group from GABA to pyruvate. While the gabT mutant and the gabT opaA double mutant grew on GABA as a nitrogen source, the final triple mutant did not. The semialdehyde released from GABA by transamination is oxidized by succinate semialdehyde dehydrogenase (GabD). Five of six potential GabD proteins in R. leguminosarum bv. viciae 3841 (GabD1, -D2, -D3, -D4, and -D5) were shown by expression analysis to have this activity. However, only mutations of GabD1, GabD2, and GabD4 were required to prevent utilization of GABA as the sole nitrogen source in culture. The specific enzyme activities of GabT, Opa, and GabD were highly elevated in bacteroids relative to cultured bacteria. This was due to elevated expression of gabT, opaA, gabD1, and gabD2 in nodules. Strains mutated in aminotransferase and succinate semialdehyde dehydrogenases (gabT, opaA, or opaB and gabD1, gabD2, or gabD4, respectively) that cannot use GABA in culture still fixed nitrogen on plants. While GABA catabolism alone is not essential for N2 fixation in bacteroids, it may have a role in energy generation and in bypassing the decarboxylating arm of the tricarboxylic acid cycle.
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PMID:Pathway of gamma-aminobutyrate metabolism in Rhizobium leguminosarum 3841 and its role in symbiosis. 1918 99

Within the second synaptic layer of the retina, bipolar cell (BC) output to ganglion cells is regulated by inhibitory input to BC axon terminals. GABA(A) receptors (GABA(A)Rs) mediate rapid synaptic currents in BC terminals, whereas GABA(C) receptors (GABA(C)Rs) mediate slow evoked currents and a tonic current, which is strongly regulated by GAT-1 GABA transporters. We have used voltage-clamp recordings from BC terminals in goldfish retinal slices to determine the source of GABA for activation of these currents. Inhibition of vesicular release with concanamycin A or tetanus toxin significantly inhibited GABA(A)R inhibitory postsynaptic currents and glutamate-evoked GABA(A)R and GABA(C)R currents but did not reduce the tonic GABA(C)R current, which was also not dependent on extracellular Ca(2+). The tonic current was strongly potentiated by inhibition of GABA transaminase, under both normal and Ca(2+)-free conditions, and was activated by exogenous taurine; however inhibition of taurine transport had little effect. The tonic current was unaffected by GAT-2/3 inhibition and was potentiated by GAT-1 inhibition even in the absence of vesicular release, indicating that it is unlikely to be evoked by reversal of GABA transporters or by ambient GABA. In addition, GABA release does not appear to occur via hemichannels or P2X(7) receptors. BC terminals therefore exhibit two forms of GABA(C)R-mediated inhibition, activated by vesicular and by nonvesicular GABA release, which are likely to have distinct functions in visual signal processing. The tonic GABA(C)R current in BC terminals exhibits similar properties to tonic GABA(A)R and glutamate receptor currents in the brain.
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PMID:Activation of the tonic GABAC receptor current in retinal bipolar cell terminals by nonvesicular GABA release. 1949 93

In tomato, free amino acids increase dramatically during fruit ripening and their abundance changed differentially. More evident is L-glutamate which gives the characteristic "umami" flavor. Glutamate is the principal free amino acid of ripe fruits of cultivated varieties. In this paper, we examined the capacity of tomato fruits to process endogenous as well as exogenous polypeptides during the ripening transition, in order to analyze their contribution to the free amino acid pool. In addition, the activity of some enzymes involved in glutamate metabolism such as gamma-glutamyl transpeptidase (gamma-GTase), glutamate dehydrogenase (GDH), alpha-ketoglutarate-dependent gamma-aminobutyrate transaminase (GABA-T), alanine and aspartate aminotransferases was evaluated. Results showed that peptidases were very active in ripening fruits, and they were able to release free amino acids from endogenous proteins and glutamate from exogenously added glutamate-containing peptides. In addition, red fruit contained enough gamma-GTase activity to sustain glutamate liberation from endogenous substrates such as glutathione. From all the glutamate metabolizing enzymes, GDH and GABA-T showed the higher increase in activities when the ripening process starts. In summary, tomato fruits increase free amino acid content during ripening, most probably due to the raise of different peptidase activities. However, glutamate level of ripe fruit seems to be mostly related to GDH and GABA-T activities that could contribute to increase L-glutamate level during the ripening transition.
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PMID:Free amino acid production during tomato fruit ripening: a focus on L-glutamate. 1987 14


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