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PubMed1977

The regulation of glutamate metabolism in Candida utilis. Evidence for two interconvertible forms of NAD-dependent glutamate dehydrogenase.

An earlier observation from this laboratory (J. Gen. Microbiol. 64, 423--427) that NAD-dependent glutamate dehydrogenase activity is modulated by rapid inactivation has been extended to show that this mechanism is completely reversible. Changes in properties of the enzyme accompany inactivation and two different forms active (a) and inactive (b) of the enzyme with distinctive properties have been isolated. Incubation of the inactive enzyme with magnesium in vitro produced a rapid increase of activity; this was accompanied by a change in the properties of the enzyme to those of the a form. This control mechanism of enzyme interconversion appears widespread among yeasts. Its probable role in modulating glutamate synthesis and degration is discussed.

Candida↗
PubMed1995

Non-glutamate type pyrrolo[2,3-d]pyrimidine antifolates. I: Synthesis and biological properties of pyrrolo[2,3-d]pyrimidine antifolates containing tetrazole congener of glutamic acid.

Either the alpha- or gamma-carboxyl group of the glutamic acid moiety of N-[4-[3-(2,4-diamino-7H-pyrrolo[2,3-d]pyrimidin-5- yl)propyl]benzoyl]-L-glutamic acid (1b, TNP-351) and its related compound (1a) was replaced with a 1H-tetrazole ring, and the inhibitory effects of the resulting compounds on dihydrofolate reductase (DHFR) and the growth of murine fibrosarcoma Meth A cells were examined. The gamma-tetrazole analogs (2) were found to be much more potent DHFR inhibitors than TNP-351, and strongly inhibited the growth of Meth A cells. On the other hand, the alpha-tetrazole analogs (3) were much less active against Meth A cells, even though their DHFR-inhibitory activity was comparable to that of TNP-351. These findings suggest that the alpha-carboxyl group plays an important role in effective uptake via the reduced folate carrier, and a novel DHFR inhibitor could be obtained by chemically modifying the gamma-carboxyl moiety while leaving the alpha-carboxyl group intact.

Animals↗
PubMed2002

Unregulated elevation of glutamate dehydrogenase activity induces glutamine-stimulated insulin secretion: identification and characterization of a GLUD1 gene mutation and insulin secretion studies with MIN6 cells overexpressing the mutant glutamate dehydrogenase.

Glutamate dehydrogenase (GDH) is important in normal glucose homeostasis. Mutations of GDH result in hyperinsulinism/hyperammonemia syndrome. Using PCR/single-strand conformation polymorphism analysis of the gene encoding GDH in 12 Japanese patients with persistent hyperinsulinemic hypoglycemia of infancy (PHHI), we found a mutation (Y266C) in one PHHI patient. This mutation was not found in any of the control or type 2 diabetic subjects. The activity of the mutant GDH (GDH266C), expressed in COS-7 cells, was constitutively elevated, and allosteric regulations by ADP and GTP were severely impaired. The effect of the unregulated increase in GDH activity on insulin secretion was examined by overexpressing GDH266C in an insulinoma cell line, MIN6. Although glutamine alone did not stimulate insulin secretion from control MIN6-lacZ, it remarkably stimulated insulin secretion from MIN6-GDH266C. This finding suggests that constitutively activated GDH enhances oxidation of glutamate, which is intracellularly converted from glutamine to alpha-ketoglutarate, a tricarboxylic acid cycle substrate, which thereby stimulates insulin secretion. Interestingly, insulin secretion is also exaggerated significantly at low glucose concentrations (2 and 5 mmol/l) but not at higher glucose concentrations (8--25 mmol/l). Our results directly illustrate the importance of GDH in the regulation of insulin secretion from pancreatic beta-cells.

Adenosine Diphosphate↗
PubMed2001

Behavioral taste similarities and differences among monosodium L-glutamate and glutamate receptor agonists in C57BL mice.

Monosodium L-glutamate (MSG) and 5'-ribonucleotides elicit umami taste in humans and probably in some species of animals. Previous studies suggest that taste-mGluR4 and NMDA receptor may be involved in taste transduction for umami, but behavioral responses in rats do not support the involvement of NMDA receptor. In the present study, behavioral similarities and differences among MSG, mGluR4 agonist L(+)-2-amino-4-phosphonobutyrate (L-AP4), and NMDA receptor agonist N-methyl-D-aspartate (NMDA) were compared in C57BL mice by using a conditioned taste aversion paradigm. Mice conditioned to avoid either MSG or 10 mM L-AP4 appeared to avoid MSG, disodium 5'-inosinate (IMP), a mixture of MSG and IMP, and L-AP4, but not NMDA. Aversive conditioning to either sucrose or NMDA was generalized only to a mixture of MSG+IMP or NaCl. However, aversive conditioning to L-AP4 at 1 mM was generalized to NMDA and the umami substances. Lick rates for L-AP4 increased by mixing with (RS)-alpha-cycloprophy-4-phosphonophenylglycine (mGluR4 antagonist) when animals were conditioned to avoid MSG or L-AP4. Lick rates for NMDA also either decreased or increased by mixing with glycine (NMDA receptor coagonist) or D(-)-2-amino-5-phosphonopentanoic acid (NMDA receptor antagonist) when animals were conditioned to avoid L-AP4 or NMDA. In sucrose-conditioned mice. gurmarin (a sweet inhibiting peptide) suppressed the avoidance of sucrose and a mixture of MSG and IMP, but not L-AP4 and NMDA. The results suggest the possibility that to C 57BL mice MSG may taste similar to L-AP4 but different from NMDA, although both types of glutamate receptors as well as gurmarin-sensitive sweet receptor may be involved in perception of umami taste.

Animals↗
PubMed2005

Highlights from the Fifth International Meeting on Metabotropic Glutamate Receptors, held September 18-23, 2005, in Taormina, Sicily, Italy. Metabotropic glutamate receptors as therapeutic targets.

The study of metabotropic glutamate receptors (mGluRs) is one of the fastest growing areas of neuropharmacology. The Fifth International Meeting on Metabotropic Glutamate Receptors, held September 18-23, 2005, in Taormina, Sicily, Italy, encompassed more than 80 oral presentations and 70 poster presentations. The role of mGluRs in various physiological and pathological conditions, such as learning and memory, modulation of sensory inputs, control of movement, schizophrenia, anxiety, seizures, addiction to drugs, neurodegeneration and developmental regulation of synaptic circuits, was discussed.

Animals↗
PubMed2006

Development of biosensor based on immobilized L-glutamate oxidase for determination of monosodium glutamate in food.

A monosodium glutamate (MSG) biosensor with immobilized L-glutamate oxidase (L-GLOD) has been developed and studied for analysis of MSG in sauces, soup etc. The immobilized enzymatic membrane was attached with oxygen electrode with a push cap system. The detection limit of the sensor was 1 mg/dl and the standard curve was found to be linear upto 20 mg/dl. Response time of the sensor was 2 min. Cross-linking with glutaraldehyde in presence of Bovine Serum Albumin (BSA) as a spacer molecule has been used for immobilization. Optimization of the sensor was done with an increase in L-GLOD concentration (6.3-31.5 IU) and also with increase in loading volume of enzyme solution (5-20 microl). Optimization of pH and temperature was also studied. The permeability of O2 through different membrane was studied with and without immobilized L-GLOD. The enzymatic membrane was used for over 20 measurements and stability of the membrane was observed.

Amino Acid Oxidoreductases↗
PubMed1987

Regional distribution of astrocytes with intense immunoreactivity for glutamate dehydrogenase in rat brain: implications for neuron-glia interactions in glutamate transmission.

The principally mitochondrial enzyme glutamate dehydrogenase (GDH) exhibited low-intensity, uniform immunoreactivity in neurons and intense heterogeneous labeling of glial cells of rat brain. Simultaneous peroxidase labeling for GDH and immunoautoradiography for glial fibrillary acidic protein (GFAP) confirmed the astrocytic localization of the enzyme. Immunoreactivity in astrocytes, but not in neurons, required the presence of Triton X-100 as a solubilizing agent. Most of the intensely labeled glial processes were localized to regions previously reported as containing moderate to high densities of binding sites for the excitatory amino acids, L-glutamate or L-aspartate, and glutamatergic fibers. These included several forebrain regions, such as the superficial layers of the rostral neocortex, dorsal neostriatum, nucleus accumbens, septohippocampal nucleus, intralaminar thalamic nuclei, and external capsules. However, the central gray of the midbrain, the nuclei of the reticular formation, brain stem regions projecting to the cerebellum, and cranial nuclei of the trigeminal and vagal nerves also exhibited intense glial labeling for GDH, even though some of these regions are known to receive only weak glutamatergic projections. A second factor determining the distribution of GDH appeared to be neuronal activity, as assessed by correspondence with reported high densities of cytochrome oxidase. We conclude that GDH enriched in glial populations exists in a subcellular compartment distinct from that of neurons and may serve as one of the enzymes involved in glutamatergic transmission. Deficiencies of glial GDH and the consequent cytotoxic effects of high levels of excitatory amino acids may contribute to a number of neurodegenerative disorders.

Animals↗
PubMed1993

Regulation of folate and one-carbon metabolism in mammalian cells. II. Effect of folylpoly-gamma-glutamate synthetase substrate specificity and level on folate metabolism and folylpoly-gamma-glutamate specificity of metabolic cycles of one-carbon metabolism.

The effect of folylpoly-gamma-glutamate synthetase (FPGS) levels on folate accumulation was investigated in Chinese hamster ovary cells expressing various levels of human and Escherichia coli FPGS activity. At low medium folate concentrations, folate accumulation was limited by influx and was independent of FPGS activity except in cells expressing extremely low levels of FPGS. Essentially all transported folate was metabolized to retained polyglutamate derivatives, the chain length of which varied with the level of FPGS activity. As medium folate concentration increased through the physiological to the pharmacological range, cellular folate accumulation became proportional to FPGS activity and the chain length of intracellular folates decreased. At high folate concentrations, competition between substrates for FPGS limited the extent of polyglutamylation and less than 5% of transported folate was retained by the cell. Pteroyltriglutamates functioned as effectively as the longer chain length polyglutamates normally found in mammalian cells in the metabolic cycles of de novo purine and thymidylate biosynthesis but were unable to support glycine and methionine synthesis. Transfectants expressing human FPGS and containing folates of glutamate chain length ranging from four to eight were equally effective at supporting glycine synthesis, and transfectants expressing higher levels of FPGS were able to grow in the absence of methionine. Growth in the absence of methionine required high (nonphysiological) intracellular folate levels and longer chain length polyglutamates.

Animals↗
PubMed2006

Glutamine synthetase-glutamate synthase pathway and glutamate dehydrogenase play distinct roles in the sink-source nitrogen cycle in tobacco.

Glutamate (Glu) metabolism and amino acid translocation were investigated in the young and old leaves of tobacco (Nicotiana tabacum L. cv Xanthi) using [15N]ammonium and [2-15N]Glu tracers. Regardless of leaf age, [15N]ammonium assimilation occurred via glutamine synthetase (GS; EC 6.1.1.3) and Glu synthase (ferredoxin [Fd]-GOGAT; EC 1.4.7.1; NADH-GOGAT; EC 1.4.1.14), both in the light and darkness, and it did not depend on Glu dehydrogenase (GDH; EC 1.4.1.2). The [15N]ammonium and ammonium accumulation patterns support the role of GDH in the deamination of [2-15N]Glu to provide 2-oxoglutarate and [15N]ammonium. In the dark, excess [15N]ammonium was incorporated into asparagine that served as an additional detoxification molecule. The constant Glu levels in the phloem sap suggested that Glu was continuously synthesized and supplied into the phloem regardless of leaf age. Further study using transgenic tobacco lines, harboring the promoter of the GLU1 gene (encoding Arabidopsis [Arabidopsis thaliana] Fd-GOGAT) fused to a GUS reporter gene, revealed that the expression of Fd-GOGAT remained higher in young leaves compared to old leaves, and higher in the veins compared to the mesophyll. Confocal laser-scanning microscopy localized the Fd-GOGAT protein to the phloem companion cells-sieve element complex in the leaf veins. The results are consistent with a role of Fd-GOGAT in supplying Glu for the synthesis and transport of amino acids. Taken together, the data provide evidence that the GS-GOGAT pathway and GDH play distinct roles in the source-sink nitrogen cycle of tobacco leaves.

Amides↗
PubMed1989

A microassay for the determination of soluble and membrane-bound glutamate decarboxylase activity--influences of cations, lipid composition, and pyridoxal 5'-phosphate on the glutamate decarboxylase binding to liposomes.

A radiochemical microassay for soluble and membrane-bound glutamate decarboxylase (GAD) is described. Up to 180 samples can be determined per day with a variation coefficient of 2%. The method detects newly synthesized gamma-amino-n-butyric acid in the picomole range and can easily be applied to other enzymes whose substrate and product differ by charge. In an aqueous homogenate of brain (1 + 10; w/v) about 15% of the total GAD activity are spun down by centrifugation (1 h, 100,000g) increasing to 35% of the total GAD activity in solutions with 8 mM calcium chloride or 100 mM potassium acetate. There is similar dependence on the cation concentration when GAD binds to phospholipid vesicles (liposomes) as well as dependence on lipid concentration and lipid composition. The coenzyme pyridoxal 5'-phosphate has no influence on GAD binding to liposomes.

Animals↗
PubMed1992

Genetically epilepsy-prone rats have increased brain regional activity of an enzyme which liberates glutamate from N-acetyl-aspartyl-glutamate.

N-Acetylated-alpha-linked acidic dipeptidase (NAALADase) is a membrane-bound peptidase which hydrolyzes the endogenous neuropeptide N-acetylaspartylglutamate (NAAG) to N-acetylaspartate (NAA) and the excitatory amino acid, glutamate (Glu). Although there is evidence that NAAG might be a neurotransmitter, this dipeptide could also function as a precursor form of Glu, which is liberated by the dipeptidase. We found that the activity of this NAAG hydrolyzing enzyme in genetically epilepsy-prone rats was 11-26% greater than control in brain regions, including the amygdala, hippocampus and cerebellum, as well as the pyriform, entorhinal and frontal cortices. This is consistent with possible increased availability of Glu in certain CNS synapses in these rats, which are reported to have increased susceptibility to audiogenically, electrically and chemically induced convulsions.

Animals↗
PubMed2005

Decreased expression of vesicular glutamate transporter 1 and complexin II mRNAs in schizophrenia: further evidence for a synaptic pathology affecting glutamate neurons.

Synaptic protein gene expression is altered in schizophrenia. In the hippocampal formation there may be particular involvement of glutamatergic neurons and their synapses, but overall the profile remains unclear. In this in situ hybridization histochemistry (ISHH) study, we examined four informative synaptic protein transcripts: vesicular glutamate transporter (VGLUT) 1, VGLUT2, complexin I, and complexin II, in dorsolateral prefrontal cortex (DPFC), superior temporal cortex (STC), and hippocampal formation, in 13 subjects with schizophrenia and 18 controls. In these areas, VGLUT1 and complexin II are expressed primarily by excitatory neurons, whereas complexin I is mainly expressed by inhibitory neurons. In schizophrenia, VGLUT1 mRNA was decreased in hippocampal formation and DPFC, complexin II mRNA was reduced in DPFC and STC, and complexin I mRNA decreased in STC. Hippocampal VGLUT1 mRNA declined with age selectively in the schizophrenia group. VGLUT2 mRNA was not quantifiable due to its low level. The data provide additional evidence for a synaptic pathology in schizophrenia, in terms of a reduced expression of three synaptic protein genes. In the hippocampus, the loss of VGLUT1 mRNA supports data indicating that glutamatergic presynaptic deficits are prominent, whereas the pattern of results in temporal and frontal cortex suggests broadly similar changes may affect inhibitory and excitatory neurons. The impairment of synaptic transmission implied by the synaptic protein reductions may contribute to the dysfunction of cortical neural circuits that characterises the disorder.

Adaptor Proteins, Vesicular Transport↗
PubMed2002

Expression of glutamate transporters and ionotropic glutamate receptors in GLAST knockout mice.

In order to investigate the molecular mechanism underlying high seizure susceptibility of GLAST knockout mice, we carried out Western blotting for the expression of GLT-1, EAAC-1, and several kinds of glutamate receptors in the hippocampus and the cortex. Although no significant difference was observed between GLAST (+/+) and (-/-) mice in terms of expression of GLT-1 and EAAC-1 in the hippocampus, these proteins were over-expressed in the frontal cortex in GLAST (-/-) mice (GLT-1, about 210% increase; EAAC-1, about 180% increase). Expression of hippocampal Glu-R1 and Glu-R2 in GLAST (-/-) mice was remarkably increased (Glu-R1, about 140% increase; Glu-R2, about 160% increase), while Glu-R3 and NMDA receptors levels (NMDA-R1, 2A and 2B) were equal to those in control. Cortical levels of Glu-R1, -R2 and -R3 receptors in GLAST (-/-) mice were remarkably decreased (Glu-R1, about 60% decrease; Glu-R2, about 60% decrease; Glu-R3, about 70% decrease), while NMDA receptors were remarkably increased in comparison to those in GLAST (+/+) mice (N-R1, about 150% increase; N-R2A, about 150% increase; N-R2B, about 140% increase). These data suggest that the increased susceptibility to seizures in GLAST (-/-) mice might be derived from increased expression of Glu-R1 in the hippocampus coupled with decreased cortical expression of Glu-R2 and increased NMDA-R1 and -2A, -2B expression.

Amino Acid Transport System X-AG↗
PubMed2006

Tobacco isoenzyme 1 of NAD(H)-dependent glutamate dehydrogenase catabolizes glutamate in vivo.

Glutamate (Glu) dehydrogenase (GDH, EC 1.4.1.2-1.4.1.4) catalyzes in vitro the reversible amination of 2-oxoglutarate to Glu. The in vivo direction(s) of the GDH reaction in higher plants and hence the role(s) of this enzyme is unclear, a situation confounded by the existence of isoenzymes comprised totally of either GDH beta- (isoenzyme 1) or alpha- (isoenzyme 7) subunits, as well as another five alpha-beta isoenzyme permutations. To clarify the in vivo direction of the reaction catalyzed by GDH isoenzyme 1, [(15)N]Glu was supplied to roots of two independent transgenic tobacco (Nicotiana tabacum) lines with increased isoenzyme 1 levels (S4-H and S49-H). The [(15)N]ammonium (NH(4)(+)) accumulation rate in these lines was elevated approximately 65% compared with a null segregant control line, indicating that isoenzyme 1 catabolizes Glu in roots. Leaf glutamine synthetase (GS) was inhibited with a GS-specific herbicide to quantify any contribution by GDH toward photorespiratory NH(4)(+) reassimilation. Transgenic line S49-H did not show enhanced resistance to the herbicide, indicating that the large pool of isoenzyme 1 in S49-H leaves was unable to compensate for GS and suggesting that isoenzyme 1 does not assimilate NH(4)(+) in vivo.

Glutamate Dehydrogenase (NADP+)↗
PubMed1994

Rapid desensitization of the metabotropic glutamate receptor that facilitates glutamate release in rat cerebrocortical nerve terminals.

The metabotropic autoreceptor of glutamatergic nerve terminals from the cerebral cortex of adult rats has been characterized. Receptor activation involves a rapid and transient increase in diacylglycerol, which is sensitive to L-2-amino-3-phosphonopropionate (L-AP3) and L-2-amino-4-phosphonobutanoic acid (L-AP4) and is partially blocked by pertussis toxin. Protein kinase C (PKC) has a negative feedback control in this transduction pathway because the activation of the kinase, either by phorbol esters or by the endogenous diacylglycerol produced by the receptor, results in a reversible receptor desensitization, with loss of the ability to further facilitate glutamate release. It is concluded that the facilitatory metabotropic receptor located at the glutamatergic nerve endings belongs to the subclass coupled to phosphoinositide hydrolysis and that the rapid and use-dependent desensitization of the facilitatory pathway may underlie a mechanism to prevent its permanent activation and thereby to avoid neurotoxicity.

Alanine↗
PubMed1987

Glutamate receptor subtypes in cultured cerebellar neurons: modulation of glutamate and gamma-aminobutyric acid release.

Using cerebellar, neuron-enriched primary cultures, we have studied the glutamate receptor subtypes coupled to neurotransmitter amino acid release. Acute exposure of the cultures to micromolar concentrations of kainate and quisqualate stimulated D-[3H]aspartate release, whereas N-methyl-D-aspartate, as well as dihydrokainic acid, were ineffective. The effect of kainic acid was concentration dependent in the concentration range of 20-100 microM. Quisqualic acid was effective at lower concentrations, with maximal releasing activity at about 50 microM. Kainate and dihydrokainate (20-100 microM) inhibited the initial rate of D-[3H]aspartate uptake into cultured granule cells, whereas quisqualate and N-methyl-DL-aspartate were ineffective. D-[3H]Aspartate uptake into confluent cerebellar astrocyte cultures was not affected by kainic acid. The stimulatory effect of kainic acid on D-[3H]aspartate release was Na+ independent, and partly Ca2+ dependent; the effect of quisqualate was Na+ and Ca2+ independent. Kynurenic acid (50-200 microM) and, to a lesser extent, 2,3-cis-piperidine dicarboxylic acid (100-200 microM) antagonized the stimulatory effect of kainate but not that of quisqualate. Kainic and quisqualic acid (20-100 microM) also stimulated gamma-[3H]-aminobutyric acid release from cerebellar cultures, and kynurenic acid antagonized the effect of kainate but not that of quisqualate. In conclusion, kainic acid and quisqualic acid appear to activate two different excitatory amino acid receptor subtypes, both coupled to neurotransmitter amino acid release. Moreover, kainate inhibits D-[3H]aspartate neuronal uptake by interfering with the acidic amino acid high-affinity transport system.

Animals↗
PubMed1996

A comparative study of the high-frequency dielectric properties of poly (alpha-glutamate) and poly (gamma-glutamate) aqueous solutions.

The dielectric properties of poly(alpha-glutamic acid) and poly(gamma-glutamic acid) aqueous solutions in the fully ionized state have been investigated in the frequency range from 1 MHz to 1 GHz by means of frequency-domain dielectric spectroscopy measurements. In this frequency range, micro-Brownian dynamics and internal motion of side-chain polar groups give rise to nonexponential relaxation processes resulting in an intermediate dielectric relaxation between that due to the counterion atmosphere polarization and that due to the orientational polarization of the water molecules. In this work, we study the influence of the polymer concentration in the dilute--semidilute regime on the dielectric parameters, i.e., the dielectric increment delta epsilon and the relaxation time tau, and discuss their relevance in the light of some scaling pictures recently proposed by Dobrynin, Colby, and Rubinstein to describe the unentangled regime of flexible polyelectrolyte solutions.

Chemical Phenomena↗
PubMed1985

Influence of ethanol upon the introduction of tyrosine aminotransferase in liver, upon the NAD content in liver and brain, and upon the activity of glutamate oxalate aminotransferase and glutamate pyruvate aminotransferase in the serum of rats.

The influence of ethanol, tryptophan, nicotinamide and methionine upon the activity of glutamate oxalate aminotransferase and glutamate pyruvate aminotransferase in serum as well as the induction of tyrosine aminotransferase in the liver, and of NAD+ + NADH in liver and brain are described. After oral application of 6 g/kg ethanol, the activities of the examined enzymes and the concentrations of NAD+ + NADH in the brain as well as in the liver did not change over a period of 8 hr. Administration of L-methionine lead--as is the case with DL-tryptophan--to a decrease of the NAD+ + NADH-concentration in the brain. A simultaneous application of nicotinamide, DL-tryptophan, L-methionine of l-methylnicotinamide together with ethanol caused a significant increase of the tyrosine aminotransferase induction in adrenalectomized animals. Ethanol reduced the activity of the ADPR transferase in the nuclei of rat liver cells.

Adrenalectomy↗