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PubMed1985

Plasma glutamate concentrations in adult subjects ingesting monosodium L-glutamate in consomme.

The effect of MSG ingestion in consomme on the plasma glutamate concentration response was studied in normal adult subjects. In the first study nine subjects ingested three different consomme servings (providing 0, 25 and 50 mg/kg body weight MSG) in a Latin square design. Plasma glutamate concentrations were not significantly increased over baseline (3.69 +/- 1.08 mumol/dl) when no added MSG was present. However, mean peak plasma glutamate levels increased proportional to dose when MSG was added (10.2 +/- 2.00 and 17.0 +/- 8.06 mumol/dl at 25 and 50 mg/kg body weight respectively). Since six of the nine subjects in this study reported an idiosyncratic symptom response when tested with MSG at 150 mg/kg body weight, nine additional subjects were also studied. They ingested consomme providing MSG at 0 and 50 mg/kg body weight. No significant differences in plasma amino acid responses were noted between the two groups of subjects.

Adult↗

PubMed1984

A kinetic study of the oxidative deamination of L-glutamate by Peptostreptococcus asaccharolyticus glutamate dehydrogenase using a variety of coenzymes.

The NAD+-specific glutamate dehydrogenase from Peptostreptococcus asaccharolyticus follows Michaelis-Menten kinetics in contrast to the enzyme from several other sources, and thus gives linear double-reciprocal plots of initial-rate data. The initial-rate parameters have been determined for this bacterial dehyrogenase in the direction of oxidative deamination. The use of alternative coenzymes leads to some conclusions about the order of substrate addition. An investigation of the pH dependence of this reaction reveals that the binding of oxidised coenzyme is independent of pH over the range 6-9. The kinetic data are consistent with an ordered addition of coenzyme prior to glutamate, the reverse of the mechanism derived with ox glutamate dehydrogenase in the presence of ADP.

Coenzymes↗

PubMed1992

Metabotropic glutamate receptors potentiate ionotropic glutamate responses in the rat dorsal horn.

The effects of the metabotropic glutamate receptor agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid [(1S,3R)-ACPD] were examined on responses mediated by the ionotropic glutamate receptor agonists N-methyl D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA), and kainic acid (KA), in neurons acutely isolated from the dorsal horn of the rat spinal cord. (1S,3R)-ACPD produced an increase in the intracellular Ca2+ concentration in 50% of acutely isolated dorsal horn neurons, which could be prevented by blockers of voltage-sensitive Ca2+ channels. (1S,3R)-ACPD markedly potentiated increases in the intracellular Ca2+ concentration induced by NMDA, AMPA, and KA but not by 10-50 mM KCl. This potentiation occurred in all cells, required the simultaneous presence of both agonists, and was rapidly reversible. In the spinal cord slice preparation, (1S,3R)-ACPD potentiated the inward currents evoked by pressure application of AMPA, NMDA, and KA, an effect that was also rapidly reversible. These short term effects of (1S,3R)-ACPD may play an important role in the regulation of ionotropic responses mediated by glutamate in the spinal cord.

Animals↗

PubMed1991

Evaluation of cysteine 283 and glutamic acid 284 in the coenzyme binding site of Salmonella typhimurium glutamate dehydrogenase by site-directed mutagenesis and reaction with the nucleotide analogue 2-[4-bromo-2,3-dioxobutyl)thio)-1,N6-ethenoadenosine 2',5'-bisphosphate.

NADP(+)-specific glutamate dehydrogenase of Salmonella typhimurium was previously shown to react irreversibly at the coenzyme site with the nucleotide analogue 2-((4-bromo-2,3-dioxobutyl)thio)-1,N6-ethenoadenosine 2',5'-bisphosphate (2-BDB-T epsilon A 2',5'-DP) yielding a partially active enzyme, and inactivation was attributed to modification of the peptide Leu282-Cys-Glu-Ile-Lys286 (Bansal, A., Dayton, M.A., Zalkin, H., and Colman, R.F. (1989) J. Biol. Chem. 264, 9827-9835). Three mutant enzymes have now been engineered, expressed in Escherichia coli, and purified: the single mutants C283I and E284Q and the double mutant C283I:E284Q. The wild-type and mutant enzymes have similar specific activities and Km values for alpha-ketoglutarate, ammonium ion, and NADPH, indicating that neither cysteine 283 nor glutamic acid 284 is essential for activity. The mutant enzyme E284Q, like wild-type glutamate dehydrogenase, is substantially inactivated by 2-BDB-T epsilon A 2',5'-DP. In contrast, the two cysteine mutant enzymes, C283I and C283I:E284Q, are not inactivated by 2-BDB-T epsilon A 2',5'-DP. Modified tryptic peptides with the sequence Leu-X-Glu(Gln)-Ile-Lys were isolated from wild-type or E284Q enzymes inactivated by 2-BDB-T epsilon A 2',5'-DP. This peptide was absent from digests of active wild-type enzyme modified in the presence of the protectant NADPH and from digests of active C283I enzyme after incubation with 2-BDB-T epsilon A 2',5'-DP. Although it is not required for catalytic activity, cysteine 283 is implicated by the results of the affinity labeling experiments as the reaction target of the nucleotide analogue and is located in the region of the coenzyme binding site.

Adenosine Diphosphate↗

PubMed1999

A poly-gamma-glutamate synthetic system of Bacillus subtilis IFO 3336: gene cloning and biochemical analysis of poly-gamma-glutamate produced by Escherichia coli clone cells.

Three genes encoding a poly-gamma-glutamate synthetic system of Bacillus subtilis IFO 3336 (Bacillus natto) were cloned and expressed in Escherichia coli. The E. coli clone produced poly-gamma-glutamate extracellularly. The genes, newly designated as pgsBCA, were homologous with capBCA genes of Bacillus anthracis. All of pgsB, pgsC, and pgsA genes were essential for the polymer production. Addition of Mn(2+), instead of Mg(2+), to the polymer-synthesis medium resulted in an increase in the polymer yield. Co-expression of glutamate racemase gene in E. coli cells harboring pgsBCA genes increased both the polymer production and D-glutamate content in the polymer. The polymer produced by the E. coli clone was higher in average molecular size than that produced by B. subtilis IFO 3336.

Amino Acid Isomerases↗

PubMedDate not supplied

Poly(alpha-alkyl gamma-glutamate)s of microbial origin. 2. On the microstructure and crystal structure of poly(alpha-ethyl gamma-glutamate)s.

The stereochemical microstructure and crystalline structure of nearly racemic poly(alpha-ethyl gamma,DL-glutamate) obtained by esterification of biosynthetic poly(gamma-glutamic acid) were examined by NMR, DSC, and powder X-ray diffraction. The two enantiomerically pure poly(alpha-ethyl gamma-glutamate)s, as well as the racemic stereocopolymers with random and alternating microstructure, were prepared by chemical synthesis and studied in parallel to help in the interpretation of the data. The (13)C NMR analysis revealed that biosynthetic poly(alpha-ethyl gamma,DL-glutamate) consists of a block stereocopolymer accompanied by minor amounts of a mixture of the two optically pure homopolymers. The polymer is crystalline, with a degree of crystallinity and crystal structure essentially similar to those displayed by the optically pure polymers but clearly different from the alternating copolymer. Conversely, the racemic stereocopolymer with a random microstructure prepared by chemical synthesis is amorphous. The crystal structure of the racemic mixture of the D- and L-homopolymers seems to be very close to that of the biosynthetic stereocopolymer, although some indications suggesting the existence of a stereocomplex were found.

Bacteria↗

PubMed1993

Glutamate Dehydrogenase Is Not Essential for Glutamate Formation by Corynebacterium glutamicum.

Two Corynebacterium glutamicum strains, one being glutamate dehydrogenase (GDH) negative and the other possessing 11-fold-higher specific GDH activity than the parental wild type, were constructed and used to analyze the role of GDH in C. glutamicum. The results indicate (i) that GDH is dispensable for glutamate synthesis required for growth and (ii) that although a high level of GDH increases the intracellular glutamate pool, the level of GDH has no influence on glutamate secretion.

Journal Article↗

PubMed1980

Pteroylpoly(gamma-glutamate) synthesis by Corynebacterium species. Studies on the mechanism of folypoly(gamma-glutamate) synthetase.

The mechanism of action of folylpolyglutamate synthetase from Corynebacterium sp. was investigated using tetrahydrofolate, MgATP, and glutamate as the substrates. Initial velocity, product inhibition, and competitive inhibition studies were consistent with an Ordered Ter Ter mechanism with MgATP binding first to the enzyme, tetrahydrofolate second, and glutamate last. The order of dissociation from the enzyme was ADP, folate, and Pi. This mechanism precludes the sequential addition of glutamate moieties to enzyme-bound folate. The Michaelis constants for (dl)-tetrahydrofolate, MgATP, and glutamate were 2,1 muM, 18 MUM, and 160 muM, respectively. Beta, gamma-Methylene-ATP was a very effective inhibitor of the reaction with an affinity for the enzyme 1 order of magnitude greater than that of ATP.

Adenosine Diphosphate↗

PubMed1988

The actions of cyclopentane analogues of glutamic acid at binding sites for kainic and glutamic acids.

The actions of the four isomers of 1-amino-1, 3-cyclopentane dicarboxylate (ACPD), a conformationally restricted analogue of glutamate, have been examined for their ability to displace radiolabelled kainate and glutamate from their binding sites on membranes prepared from rat brain. All four of the isomers reduced specific kainate binding, and all enhanced that of glutamate although one (D-(-)-cis-(1R,3R)-ACPD) was significantly more active in this respect than were the other three. The results are discussed in terms of the pharmacological effects of the isomers of ACPD on single neurones and the possible structural requirements of the NMDA and kainate receptors.

Amino Acids↗

PubMed1995

Metabotropic glutamate receptor agonists inhibit endogenous glutamate release from rat striatal synaptosomes.

A striatal synaptosomal preparation was used to assess the action of metabotropic glutamate receptor (mGlu receptor) agonists on 4-aminopyridine (2 mM)-stimulated endogenous glutamate release. 4-Aminopyridine alone increased basal glutamate release by 6.89 +/- 0.74 nmol/mg. The mGlu receptor agonists L-2-amino-4-phosphonobutyric acid (L-AP4) (IC50 approximately 0.2 microM) and (1S,3S)-1-amino-cyclopentane-1,3-dicarboxylic acid (IC50 approximately 0.2 microM) inhibited 4-aminopyridine-stimulated release. The putative mGlu receptor antagonist (S)-alpha-methyl-L-AP4, which itself inhibited 4-aminopyridine-stimulated release (IC50 approximately 10 microM), did not inhibit the effects of the two agonists.

4-Aminopyridine↗

PubMed1985

Kinetic studies of ox-liver glutamate dehydrogenase oxidative deamination of two glutamate analogues, L-threo-gamma-methylglutamate and L-alpha-amino-gamma-nitraminobutyrate, in the presence of the allosteric effector ADP.

Ox-liver glutamate dehydrogenase is known to utilise a wide range of amino acid substrates. Kinetic studies are presented here for L-threo-gamma-methylglutamate and L-alpha-amino-gamma-nitraminobutyrate in the presence of the allosteric effector ADP. The results presented are considered in the light of similar studies presented elsewhere in which the cofactor was systematically replaced by a variety of analogues. These amino acid analogues share the same pH optimum as glutamate, unlike the monocarboxylic amino acids including alanine and norvaline, and give linear double-reciprocal plots under the conditions used here. Studies with the alternative coenzymes have suggested an ordered addition of glutamate before coenzyme in the presence of ADP. The present results obtained under identical conditions support this conclusion.

Adenosine Diphosphate↗

PubMed2005

Glutamate-based therapeutic approaches: targeting the glutamate transport system.

Although the ionotropic and metabotropic receptors for synaptically released glutamate have been extensively mined in the pursuit of novel therapeutic agents for a diverse array of central nervous system disorders, pursuit of the transport proteins--or excitatory amino acid transporters (EAATs)--toward a similar end has been a road much less travelled. Recent progress has seen the use of cloned EAAT subtypes to develop transporter inhibitors with improved subtype selectivity, providing important tools for elucidating the precise contribution of each transporter subtype to the regulation of extracellular glutamate homeostasis. In addition, momentum has been gained with the discovery of compounds capable of upregulating the activity of the predominant forebrain glutamate transporter, EAAT2.

Animals↗

PubMed2006

Hypolocomotion in rats with chronic liver failure is due to increased glutamate and activation of metabotropic glutamate receptors in substantia nigra.

BACKGROUND/AIMS: Patients with hepatic encephalopathy show altered motor function, psychomotor slowing and hypokinesia. The underlying mechanisms remain unclear. This work's aims were: (1) to analyse in rats with chronic liver failure due to portacaval shunt (PCS) the neurochemical alterations in the basal ganglia-thalamus-cortex circuits; (2) to correlate these alterations with those in motor function and (3) to normalize motor activity of PCS rats by pharmacological means. METHODS: Extracellular neurotransmitters levels were analysed by in vivo brain microdialysis. Motor activity was determined by counting crossings in open field. RESULTS: Extracellular glutamate is increased in substantia nigra pars reticulata (SNr) of PCS rats. Blocking metabotropic receptor 1 (mGluR1) in SNr normalizes motor activity in PCS rats. In ventro-medial thalamus of PCS rats GABA is increased and it is normalized by blocking mGluR1 in SNr. Blocking mGluR1 in SNr increases and mGluR1 activation reduces glutamate in motor cortex and motor activity. CONCLUSIONS: Increased extracellular glutamate and activation of mGluR1 in SNr are responsible for reduced motor activity in rats with chronic liver failure. Blocking mGluR1 in SNr normalizes motor activity in PCS rats, suggesting that, under appropriate conditions, similar treatments could be useful to treat the psychomotor slowing and hypokinesia in patients with hepatic encephalopathy.

Animals↗

PubMed2005

Down-regulation of the glial glutamate transporter GLT-1 in rat hippocampus and striatum and its modulation by a group III metabotropic glutamate receptor antagonist following transient global forebrain ischemia.

Our goals were to identify biochemical markers for transient global ischemia-induced delayed neuronal death and test possible drug therapies against this neuronal damage. Four-vessel occlusion (4-VO) for 20 min was used as a rat model. The temporal expression profiles of three glutamate transporters (GLT-1, GLAST and EAAC1) were evaluated in the CA1 region of the hippocampus and the striatum. The protein levels of the GLT-1 were significantly down-regulated between 3 and 6 h after ischemia-reperfusion in the CA1 region and striatum, returned to the control (2-VO) levels 24 h after reperfusion and remained unchanged for up to 7 days. The levels of GLAST in the CA1 region and striatum, and EAAC1 in the CA1 region did not change after ischemia from 1 h to 7 days. Pretreatment with group III metabotropic glutamate receptor antagonist s-alpha-MCPA (20 microg/5 microl) 30 min prior to 4-VO significantly restored the GLT-1 levels in the CA1 region caused by global ischemia at both 3 and 6 h after reperfusion. The loss of pyramidal neurons in the CA1 region due to ischemia-reperfusion could also be prevented by intraventricular pretreatment with s-alpha-MCPA. The current findings pinpoint the significance of GLT-1 during ischemia/reperfusion and suggest a potential application of group III metabotropic glutamate receptor antagonist against ischemic/hypoxic neuronal damage.

2-Methyl-4-chlorophenoxyacetic Acid↗

PubMed2001

Effects of glutamate receptor agonist on extracellular glutamate dynamics during moderate cerebral ischemia.

We performed real-time monitoring of the extracellular glutamate dynamics in the rat striatum in vivo using the microdialysis electrode technique, during an experimental penumbral condition of moderate global cerebral ischemia and activated glutamate receptors. The local cerebral blood flow (CBF) was measured with a laser-Doppler probe. One minute after bilateral common carotid artery occlusion (BCAO), CBF was reduced to approximately 60% of the pre-ischemic value and it remained at this level during the period of occlusion. After BCAO, a transient depolarization and a transient increase in extracellular glutamate concentration ([Glu]e) were seen. In other rats, 500 microM N-methyl-D-aspartate (NMDA) was locally micro-transfused for 30 min prior to BCAO. Upon induction of BCAO, an anoxic depolarization-like depolarization and a gradual increase in [Glu]e that continued over the duration of BCAO were seen. After BCAO was terminated, the direct current (DC) rapidly recovered to the basal level, while [Glu]e gradually decreased to the basal level. In rats that were locally micro-transfused with 500 microM Kainate prior to BCAO, DC and [Glu]e did not differ significantly from control. Pretreatment with MK-801 prior to NMDA treatment completely inhibited the NMDA-induced changes in DC and [Glu]e. Pretreatment with NBQX prior to NMDA treatment did not inhibit the NMDA-induced changes in DC and [Glu]e. Consequently, we found that activation of NMDA receptors by elevated [Glu]e exerts an important effect on [Glu]e dynamics in the spreading stroke region very early in the acute stage of cerebral ischemia in vivo.

Animals↗

PubMed1998

High potassium-induced glutamate release in the cochlea: in vivo microdialysis study combined with on-line enzyme fluorometric detection of glutamate.

The time course of changes in perilymphatic glutamate release and their Ca2+-dependency were studied in the guinea pig cochlea during high K+-evoked depolarization. The glutamate concentration was analyzed continuously by an enzyme-linked fluorometric assay combined with microdialysis. Two peaks of glutamate increase were found in response to perfusion for 10 min. In the absence of Ca2+, the first peak was diminished, whereas the inhibition of the second peak was minimal.

Animals↗

PubMed1981

Irreversible inhibition of glutamate decarboxylase by alpha-(fluoromethyl)glutamic acid.

alpha-(Fluoromethyl)glutamic acid (FMG) was synthesized and shown to be an active site directed irreversible inhibitor of glutamate decarboxylase (EC 4.1.1.15) from Escherichia coli. The KI for the active enantiomer is 1.4 microM, and the kinh = 5.9 X 10(-3) s-1. Substrates for the enzyme, such as L-glutamate, and competitive inhibitors, such as citrate, decrease the rates of FMG-mediated inactivation of the enzyme. A profound change in the ultraviolet spectrum of the enzyme accompanies the inactivation process. When [3H]-FMG is used, it can be shown that the enzyme incorporates radioactivity at the same rate as that of inactivation. There is a 1:1 stoichiometry of [3H]FMG incorporated to pyridoxal phosphate binding subunits of the enzyme. From these and other studies it is concluded that FMG is a substrate for the enzyme and alkylates it as a consequence of this turnover.

Binding, Competitive↗

PubMed1978

Effect of ammonia on the glutamate dehydrogenase catalyzed oxidative deamination of L-glutamate: production of an ammonia-containing intermediate in the "burst" phase.

We have studied the effects of ammonium acetate on the transient "burst" phase of the oxidation of L-glutamate by glutamate dehydrogenase. Two measurable changes are observed in the "burst" phase as ammonium acetate concentration is increased: (i) an increase in the apparent first-order rate constant, kapp, and (ii) a decrease in the amplitude of the absorbance change measured at 320 nm. The increase in kapp shows a hyperbolic dependence on ammonium acetate concentration and is independent of glutamate concentration. The results demonstrate the existence of an intermediate immediately following hydrogen transfer. The intermediate contains enzyme, reduced coenzyme, ammonia, and alpha-ketoglutarate moieties and is in equilibrium with the known complex consisting of enzyme, reduced coenzyme, and alpha-ketoglutarate. At high concentrations of ammonium acetate, the equilibrium favors the ammonia containing complex.

Ammonia↗