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PubMed1990

Role of arginine 180 and glutamic acid 177 of ricin toxin A chain in enzymatic inactivation of ribosomes.

The gene for ricin toxin A chain was modified by site-specific mutagenesis to change arginine 180 to alanine, glutamine, methionine, lysine, or histidine. Separately, glutamic acid 177 was changed to alanine and glutamic acid 208 was changed to aspartic acid. Both the wild-type and mutant proteins were expressed in Escherichia coli and, when soluble, purified and tested quantitatively for enzyme activity. A positive charge at position 180 was found necessary for solubility of the protein and for enzyme activity. Similarly, a negative charge with a proper geometry in the vicinity of position 177 was critical for ricin toxin A chain catalysis. When glutamic acid 177 was converted to alanine, nearby glutamic acid 208 could largely substitute for it. This observation provided valuable structural information concerning the nature of second-site mutations.

Animals↗
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↗
PubMed1992

[Effect of metabolic stress on the release of glutamic acid and GABA in the brain tissue of Mongolian hamsters].

The concentrations of glutamic acid and GABA were determined in the brain tissue in gerbils under conditions simulating "metabolic stress", that is ischaemia, aglycaemia and anoxia. The material for the determinations was taken from fragments of the hippocampus incubated under these conditions in artificial cerebrospinal fluid, and the concentrations of these neurotransmitters were determined by histochemical methods in vitro. The release of glutamic acid and GABA into the extracellular space increased with longer duration of the incubation in a linear fashion in all experimental groups and was most pronounced in ischaemia. In case of calcium absence in the extracellular space inhibition was observed of the release of these neurotransmitters which suggested an important role of bivalent cations in the regulation of the studied process, especially under control conditions. During anoxia and ischaemia a considerable part of the release of glutamic acid and GABA seems to be calcium-independent which may suggest presence of additional sources of release of the amino acid neurotransmitters, apart from their release from the direct pool. It is possible that these sources are activated during metabolic stress involving nerve cells.

Animals↗
PubMed2001

Stability and CTL activity of N-terminal glutamic acid containing peptides.

Several cytotoxic T lymphocyte peptide-based vaccines against hepatitis B, human immunodeficiency virus and melanoma were recently studied in clinical trials. One interesting melanoma vaccine candidate alone or in combination with other tumor antigens, is the decapeptide ELA. This peptide is a Melan-A/MART-1 antigen immunodominant peptide analog, with an N-terminal glutamic acid. It has been reported that the amino group and gamma-carboxylic group of glutamic acids, as well as the amino group and gamma-carboxamide group of glutamines, condense easily to form pyroglutamic derivatives. To overcome this stability problem, several peptides of pharmaceutical interest have been developed with a pyroglutamic acid instead of N-terminal glutamine or glutamic acid, without loss of pharmacological properties. Unfortunately compared with ELA, the pyroglutamic acid derivative (PyrELA) and also the N-terminal acetyl-capped derivative (AcELA) failed to elicit cytotoxic T lymphocyte (CTL) activity. Despite the apparent minor modifications introduced in PyrELA and AcELA, these two derivatives probably have lower affinity than ELA for the specific class I major histocompatibility complex. Consequently, in order to conserve full activity of ELA, the formation of PyrELA must be avoided. Furthermore, this stability problem is worse in the case of clinical grade ELA, produced as an acetate salt, like most of the pharmaceutical grade peptides. We report here that the hydrochloride salt, shows higher stability than the acetate salt and may be suitable for use in man. Similar stability data were also obtained for MAGE-3, another N-terminal glutamic acid containing CTL peptide in clinical development, leading us to suggest that all N-terminal glutamic acid and probably glutamine-containing CTL peptide epitopes may be stabilized as hydrochloride salts.

Animals↗
PubMed1979

Excretion of glutamic acid in Citrobacter intermedius C3 associated with plasmid deoxyribonucleic acid.

Several mutants of Citrobacter intermedius C3 lacking both the ability to synthesize proline and the ability to excrete glutamic acid were isolated by treatment with nitrosoguanidine. No revertants for either characteristic were obtained from these mutants. The ability to excrete glutamic acid was transferred to those mutants with very high frequencies in mating experience by using auxotropic excreting strains as donors. Moreover, the ability to synthesize proline was transferred together with the ability to excrete glutamic acid when an excreting strain was used as donor. The transconjugants showed a rapid spontaneous curing of both genetic markers. It was shown by two different methods that a band of covalently closed circular deoxyribonucleic acid is present in the cesium chloride gradients corresponding to the wild type and excretor mutants. Nonexcretor mutants described herein lacked such a band. Pro + transformants that were also excretors were obtained with plasmid deoxyribonucleic acid isolated either from wild type or from an excretor mutant. These data strongly indicate that glutamic acid excretion in C. intermedius C3 is related to the presence of extrachromosomal deoxyribonucleic acid.

Citrobacter↗
PubMed1975

Effect of glutamic acid on the fatty acid and lipid composition of Choanephora cucurbitarum.

The fatty acid composition of the total, neutral, sterol, free fatty acid, and polar-lipid fractions in the mycelium of Choanephora curcurbitarum was determined. The major fatty acids in all lipid fractions were palmitic, oleic, linoleic, and gamma-linolenic acid. Different lipid fractions did not show any particular preference for any individual fatty acid; however, the degree of unsaturation was different in different lipid fractions. Free fatty acid and polar lipid fractions contained a higher proportion of gamma-linolenic acid than did triglyceride and sterol fractions. Addition of glutamic acid to the malt-yeast extract and medium resulted in the biosynthesis of a number of long-chain fatty acids beyond the gamma-linolenic acid. These fatty acids, e.g., C22:1, C24:0, and C26:0, were never observed to be present in the fungus when grown on a malt-yeast extract medium without glutamic acid. Furthermore, thin-layer chromatographic analysis showed a larger and denser spot of diphosphatidyl glycerol from the mycelium grown on glutamic acid medium than from the control mycelium. The possible significance of this finding is discussed.

Culture Media↗
PubMed1991

Distribution of glutamic acid decarboxylase (Mr 67,000) in the basal ganglia of the rat: an immunohistochemical study with a selective cDNA-generated polyclonal antibody.

Distinct isoforms of glutamic acid decarboxylase, the synthetic enzyme for GABA, exist in brain. Their distribution at the cellular level is not known, because previous studies have been confounded by the lack of monospecificity of available antibodies. We have examined the distribution of glutamic acid decarboxylase (Mr 67,000; GAD67) in the basal ganglia of the rat with a polyclonal antibody generated against the protein expressed in bacteria transformed with the corresponding cDNA. This antibody, which is directed against a portion of GAD67 non homologous to other known glutamic acid decarboxylase isoforms, selectively recognizes GAD67 on western blots. We show that GAD67 is present to various degree in all types of GABAergic neurons previously described in these regions. In contrast with results obtained with non-selective antibodies for glutamic acid decarboxylase, GAD67-positive neuronal cell bodies were readily detected in sections of the striatum, pallidum and substantia nigra in the absence of colchicine treatment. Modifications in the immunohistochemical procedure favoured staining of glutamic acid decarboxylase-positive fibres with the same antibody, indicating that GAD67 is also present in axon terminals of GABAergic neurons. The results suggest that GAD67 may be involved in GABA synthesis in both cell bodies and axon terminals of all GABAergic neurons of the basal ganglia, but is particularly abundant or accessible in their cell bodies.

Animals↗
PubMed1992

Contrasting patterns in the localization of glutamic acid decarboxylase and Ca2+/calmodulin protein kinase gene expression in the rat central nervous system.

The expression of the genes encoding the alpha subunit of type II calcium calmodulin-dependent protein kinase (CaM II kinase alpha) and the 67,000 mol. wt form of glutamic acid decarboxylase was examined throughout the rat central nervous system. In situ hybridization histochemistry, using cRNA probes, revealed a dense population of CaM II kinase alpha-expressing cells throughout the telencephalon and diencephalon. CaM II kinase alpha mRNA was also expressed in the midbrain, cerebellum and medulla oblongata, but at greatly reduced levels. No CaM II kinase alpha gene expression was detected in nuclei producing monoamines or acetylcholine. By contrast, the glutamic acid decarboxylase gene was moderately to highly expressed throughout the central nervous system. In several regions there was a complementarity in the distributions of cells expressing the glutamic acid decarboxylase or CaM II kinase alpha genes. Cells in certain nuclei such as the thalamic reticular nucleus or globus pallidus showed glutamic acid decarboxylase gene expression only; others such as the majority of the dorsal thalamic nuclei showed CaM II kinase alpha gene expression only. Several regions contained both glutamic acid decarboxylase and CaM II kinase alpha expressing cells. However, simultaneous immunostaining for both proteins revealed only two regions where CaM II kinase alpha and glutamic acid decarboxylase immunoreactivity were colocalized: the cerebellar Purkinje cells and the commissural nucleus of the stria terminalis. The results imply that CaM II kinase alpha is primarily expressed in non-GABAergic neurons. In several regions CaM II kinase alpha mRNA is concentrated in nuclei known to contain populations of neurons that use excitatory amino acid transmitters.

Animals↗
PubMed1991

The identification of a new heterocyclic amine mutagen from a heated mixture of creatine, glutamic acid and glucose.

A new heterocyclic amine mutagen was isolated from a dry-heated reaction of the natural meat components creatine, glutamic acid and glucose. Heating creatine and glutamic acid alone had only one seventh of the Ames/Salmonella mutagenic activity of the glucose, creatine and glutamic acid mixture. The major mutagenic compound was purified by HPLC using the Ames/Salmonella test to guide the purification. The mutagen has a molecular weight of 244 and a composition of C12H12N4O2 as determined by high-resolution mass spectrometry. NMR and IR spectral data suggest the structure is a 2,6-diamino-3,4-dimethyl-7-oxo-pyrano[4,3-g]benzimidazole. Mutagenic activity in strains TA1538, TA98 and TA100, was approximately 7000, 5200, and 550 revertants per microgram, respectively. The formation of this mutagen from natural meat components suggests that it may be present in cooked food. The preferential formation of this mutagen with glucose shows that glucose can be important in dry-heated mutagen-forming reactions.

Chromatography, High Pressure Liquid↗
PubMed1998

Role of glutamic acid residues 154, 155, and 165 of lecithin:cholesterol acyltransferase in cholesterol esterification and phospholipase A2 activities.

Previous studies have shown that cholesterol esterification activity by lecithin:cholesterol acyltransferase (LCAT) is progressively inhibited as up to three acidic acid residues are chemically modified. The purpose of this study was to determine whether three glutamic acid residues in LCAT (154, 155, and 165), that align exactly with three acidic acid residues (270, 271, and 281) in the amphipathic phospholipid binding region of apoE, were necessary for enzymatic activity. Site-directed mutagenesis was used to generate mutant constructs of LCAT in which glutamic acid residues 154, 155, and 165 were replaced with glutamine or lysine. Media harvested from transiently transfected COS cells was used as a source of LCAT for cholesterol esterification and phospholipase A2 (PLA2) assays. Cholesterol esterification for all mutant constructs (11-26 nmol CE/h/microg) was similar to or greater than that of wild type LCAT (16 nmol CE/h/microg), except for a triple mutant, in which glutamic acid residues 154, 155, and 165 were changed to lysines (5 nmol CE/h/microg). PLA2 activity followed a similar trend. There was a significant decrease in the cholesterol esterification to PLA2 activity ratio when residue 165 was mutated from its wild type negative charge (E) to an uncharged (Q) or positive (K) charged residue (10.2 vs. 6.0 vs. 4.3, respectively). We conclude that glutamic acid residues 154, 155, and 165 individually or collectively are not necessary for LCAT activity and that residue 165 may be in a region of LCAT that is involved with cholesterol binding or is sensitive to cholesterol binding at the active site of the enzyme.

Amino Acid Sequence↗
PubMed2000

Identification of catalytic nucleophile of Escherichia coli gamma-glutamyltranspeptidase by gamma-monofluorophosphono derivative of glutamic acid: N-terminal thr-391 in small subunit is the nucleophile.

gamma-Glutamyltranspeptidase (EC 2.3.2.2) is the enzyme involved in glutathione metabolism and catalyzes the hydrolysis and transpeptidation of gamma-glutamyl compounds such as glutathione and its derivatives. The reaction is thought to proceed via a gamma-glutamyl-enzyme intermediate where a hitherto unknown catalytic nucleophile is gamma-glutamylated. Neither affinity labeling nor site-directed mutagenesis of conserved amino acids has succeeded so far in identifying the catalytic nucleophile. We describe here the identification of the catalytic nucleophile of Escherichia coli gamma-glutamyltranspeptidase by a novel mechanism-based affinity labeling agent, 2-amino-4-(fluorophosphono)butanoic acid (1), a gamma-phosphonic acid monofluoride derivative of glutamic acid. Compound 1 rapidly inactivated the enzyme in a time-dependent manner (k(on) = 4.83 x 10(4) M(-1) s(-1)). The inactivation rate was decreased by increasing the concentration of the substrate. The inactivated enzyme did not regain its activity after prolonged dialysis, suggesting that 1 served as an active-site-directed affinity label by phosphonylating the putative catalytic nucleophile. Ion-spray mass spectrometric analyses revealed that one molecule of 1 phosphonylated one molecule of the small subunit. LC/MS experiments of the proteolytic digests of the phosphonylated small subunit identified the N-terminal peptide Thr391-Lys399 as the phosphonylation site. Subsequent MS/MS experiments of this peptide revealed that the phosphonylated residue was Thr-391, the N-terminal residue of the small subunit. We conclude that the N-terminal Thr-391 is the catalytic nucleophile of E. coli gamma-glutamyltranspeptidase. This result strongly suggests that gamma-glutamyltranspeptidase is a new member of the N-terminal nucleophile hydrolase family.

Aminobutyrates↗
PubMedDate not supplied

[The effect of glutamic acid on the defensive and feeding behavior of the snail Helix lucorum].

Behavioural effects of glutamic acid injection into the body cavity were investigated in the land snail Helix lucorum. An injection itself induced some non-coordinated defensive reactions leading to a partial withdrawal into a shell. The defensive tentacle reflex was facilitated probably due to an activation of the tentacle muscles. The defensive reflex of the pneumostome closure changed in different directions depending on the injected dose of glutamic acid. Feeding behaviour was inhibited by a high dose of glutamic acid. The most pronounced inhibition of the feeding behaviour was induced by N-methyl-DL-aspartic acid.

Animals↗
PubMed1991

Peripheral inflammation is associated with increased glutamic acid decarboxylase immunoreactivity in the rat spinal cord.

We have examined the frequency and distribution of neuron profiles immunoreactive for glutamic acid decarboxylase, a biosynthetic enzyme for the putative inhibitory neurotransmitter, gamma aminobutyric acid, in the lumbar spinal cord of colchicine-treated rats with unilateral inflammation of a hindpaw. Ipsilateral to the inflamed hindpaw, there was an apparent increase in the levels of glutamic acid decarboxylase, as indicated by significant increases in the number of visible glutamic acid decarboxylase-like immunoreactive profiles within the superficial dorsal horn, neck of the dorsal horn and the deep gray matter at L4. An increase limited to the deep gray matter at L6 was also seen. No alteration was identified at L2. These results are the first to demonstrate that peripheral inflammation is associated with altered levels of glutamic acid decarboxylase-like immunoreactivity.

Animals↗