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PubMed1981

Metabolic activation of glutamic acid pyrolysis products, 2-amino-6-methyldipyrido[1,2-a:3',2'-d]imidazole and 2-amino-dipyrido[1,2-a:3',2'-d]imidazole, by purified cytochrome P-450.

Metabolic activation by cytochrome P-450 of glutamic acid pyrolysis products, 2-amino-6-methyldipyrido(1,2-a:3',2'-d)imidazole (Glu-P-1) and 2-amino-dipyrido(1,2,-a:3',2'-d)imidazole (Glu-P-2), to mutagenic metabolites was studied using Salmonella typhimurium TA98 as a tester strain. Cytochrome P-450, NADPH-cytochrome P-450 reductase and NADPH were essential requirements for the activation of these compounds. Of the four forms of cytochrome P-450 examined, polychlorinated biphenyls (PCB) P-448 and 3-methylcholanthrene (MC) P-448 purified from liver microsomes of rats treated with a PCB mixture and MC, respectively, showed high activity in the activation of both Glu-P-1 and Glu-P-2. The presence of three metabolites from Glu-P-1 or Glu-P-2 was demonstrated by high performance liquid chromatographic (HPLC) analysis. Among the metabolites of Glu-P-1, two metabolites were mutagenic without any further enzymatic activation. In accordance with the results of a mutation assay, PCB P-448 also exhibited higher activity to form the major mutagenic metabolite of Glu-P-1. The major active metabolite of Glu-P-1 was characterized as N-hydroxy-Glu-P-1 by chemical analysis using oxidizing and reducing reagents and by mass spectrometry.

Animals↗
PubMed1999

Process of carboxylation of glutamic acid residues in the gla domain of human des-gamma-carboxyprothrombin.

In the absence of vitamin K (VK) or in the presence of VK antagonists, hepatic VK-dependent carboxylase activity is inhibited and des-gamma-carboxyprothrombin (DCP) is released into the blood. We analyzed the number of glutamic acid (Glu) residues and their positions in the Gla domain (GD) of DCP to investigate the gamma-carboxylation mechanism of VK-dependent carboxylase. Several DCPs were found in each subject studied. The 10 Gla residues of human prothrombin were carboxylated in order from the N-terminal (residues 26, 25, 16, 29, 20, 19, 14, 32, 7 and 6). The process of Glu carboxylation seemed to proceed three-dimensionally from inside to outside the molecule.

Adult↗
PubMed1984

Induction of cancers in the intestine, liver and various other organs of rats by feeding mutagens from glutamic acid pyrolysate.

The mutagenic compounds 2-amino-6-methyldipyrido[1,2-alpha:3',2'-d]imidazole (Glu-P-1) and 2- aminodipyrido [1,2-alpha: 3',2'-d]imidazole (Glu-P-2), which were isolated from a glutamic acid pyrolysate and are potent carcinogens in the liver and brown adipose tissue of mice, were found to be multipotent carcinogens in rats. These compounds were each given to F344 rats of both sexes at a concentration of 500 ppm in pellet diet for up to 24 months. Glu-P-1 induced tumors in the colon, small intestine, liver, Zymbal gland, clitoral gland and brain. Glu-P-2 produced tumors in the same sites at slightly lower incidence. The multipotent carcinogenicities of Glu-P-1 and Glu-P-2 in rats and mice suggest that heterocyclic amines present in cooked food may be important in the development of human cancer.

Adenocarcinoma↗
PubMed2005

Neonatal hyperammonemia: the N-carbamoyl-L-glutamic acid test.

In a prospective study, patients with a suspected urea cycle defect underwent oral N-carbamoyl-L-glutamic acid loading testing. In patients with subsequently confirmed N-acetylglutamate synthase deficiency, hyperammonemia normalized within 8 hours. This test may be useful in the early diagnosis of patients with suspected urea cycle disorders.

Acetyltransferases↗
PubMed1992

A single base mutation in the gene for type III collagen (COL3A1) converts glycine 847 to glutamic acid in a family with Ehlers-Danlos syndrome type IV. An unaffected family member is mosaic for the mutation.

Ehlers-Danlos syndrome type IV, an inherited connective tissue disease, is usually caused by mutations in the gene for type III collagen. Here, we describe a glycine to glutamic acid substitution in a patient with this syndrome. Previous studies had shown that fibroblasts from the patient, his mother and brother secreted a reduced amount of type III collagen and also produced an overmodified form of the protein that was preferentially retained intracellularly. Peptide mapping experiments indicated that the mutation was located within cyanogen bromide peptide 9. This was supported by chemical cleavage analysis and sequencing of cDNA encoding this region. Allele-specific oligonucleotide hybridisation of genomic DNA confirmed that a G to A mutation converted Gly 847 to Glu. The mutation was present in two other affected family members and also in a third, who was clinically unaffected. Further analysis of this unaffected individual revealed reduced mutant:normal ratios in DNA obtained from both blood and hair samples, showing that she was mosaic for the mutation.

Amino Acid Sequence↗
PubMed1987

Neuroleptic-induced oral dyskinesias: effects of progabide and lack of correlation with regional changes in glutamic acid decarboxylase and choline acetyltransferase activities.

The development of vacuous chewing movements (VCMs), and changes in glutamic acid decarboxylase (GAD) and choline acetyltransferase (ChAT) activities in extrapyramidal nuclei were examined in rats treated chronically with neuroleptics. Animals were injected with flupenthixol (FLU) or haloperidol (HAL) decanoate for 16, 40 or 48 weeks and were then sacrificed. Another group of rats was treated with FLU or HAL for 48 weeks, and then withdrawn from the neuroleptics for 16 weeks before sacrifice. VCMs were assessed weekly, and the effects of the GABA agonist progabide on VCMs and locomotor activity were examined. GAD and ChAT activities were determined at death. The concentrations of Calbindin D28K (CaBP) and parvalbumin (PV) were determined in rats receiving 48 weeks of neuroleptic treatment. VCMs first appeared after 8-10 weeks of neuroleptic administration, reached asymptotic rates after 18-20 weeks, and then remained stable for the remainder of the chronic drug administration period. During withdrawal, there was a steady decline in the VCM rate. The GABA receptor agonist progabide reduced VCMs and locomotor activity. Significant decreases in nigral GAD activity were observed after 40, but not after either 16 or 48 weeks of neuroleptic administration. CaBP and PV were unchanged after 48 weeks of neuroleptic treatment. In addition, ChAT activities in 16, 40 or 48 week treated animals did not show consistent changes after either neuroleptic. Chronic neuroleptic administration followed by 16 weeks of withdrawal also did not have any significant effects on GAD or ChAT activity in any of the brain areas examined.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Rat brain glutamic acid decarboxylase sequence deduced from a cloned cDNA.

A cDNA clone complementary to the rat brain glutamic acid decarboxylase mRNA was isolated from a rat brain cDNA expression library using an antibody specific to the enzyme. The cDNA insert has been shown to direct the synthesis of an active protein in Escherichia coli. In this study, the nucleotide sequence of this clone, which includes the complete coding region, is presented. The predicted protein is 593 amino acids in length. The first 557 residues display a 95% identity when compared with the corresponding cat sequence. However, the deduced amino acid sequence of the carboxy-terminal end of the rat protein, downstream of residue 557, is totally different from the cat, whereas it agrees with a published partial peptidic sequence of the rat protein.

Animals↗
PubMed2005

The human chorionic gonadotropin-beta arginine68 to glutamic acid substitution fixes the conformation of the C-terminal peptide.

Wild-type human chorionic gonadotropin (hCG) has been used as a contraceptive vaccine. However, extensive sequence homology with LH elicits production of cross-reactive antibodies. Substitution of arginine(68) of the beta-subunit (hCG(beta)) with glutamic acid (R68E) profoundly reduces the cross-reactivity while refocusing the immune response to the hCG(beta)-specific C-terminal peptide (CTP). To investigate the molecular basis for this change in epitope usage, we immunized mice with a plasmid encoding a truncated hCG(beta)-R68E chain lacking the CTP. The animals produced LH-cross-reactive antibodies, suggesting that the refocused immunogenicity of R68E is a consequence of epitope masking by a novel disposition of the CTP in the mutant rather than a structural change in the cross-reactive epitope region. This explanation was strongly supported by surface plasmon resonance analysis using a panel of anti-hCG(beta)-specific and anti-hCG(beta)/LH cross-reactive monoclonal antibodies (mAbs). Whereas the binding of the LH cross-reactive mAbs to hCG(beta)-R68E was eliminated, mAbs reacting with hCG(beta)-specific epitopes bound to hCG(beta) and hCG(beta)-R68E with identical affinities. In a separate series of experiments, we observed that LH cross-reactive epitopes were silent after immunization with a plasmid encoding a membrane form of hCG(beta)-R68E, as previously observed with the soluble mutant protein itself. In contrast, the plasmid encoding the soluble secreted form of hCG(beta)-R68E evoked LH cross-reactive antibodies, albeit of relatively low titer, suggesting that the handling and processing of the proteins produced by the two constructs differed.

Amino Acid Substitution↗
PubMed1997

Molybdenum(VI) Peroxo alpha-Amino Acid Complexes: Synthesis, Spectra, and Properties of MoO(O(2))(2)(alpha-aa)(H(2)O) for alpha-aa = Glycine, Alanine, Proline, Valine, Leucine, Serine, Asparagine, Glutamine, and Glutamic Acid. X-ray Crystal Structures of the Glycine, Alanine, and Proline Compounds.

The compounds MoO(O(2))(2)(alpha-aa)(H(2)O), alpha-aa = glycine (1), alanine (2), proline (3), valine (4), leucine (5), serine (6), asparagine (7), glutamine (8), and glutamic acid (9), were prepared from the acidic aqueous solutions and characterized by examination of their IR, (1)H and (13)C NMR, and UV-visible spectra. They represent the first complexes containing a peroxo-alpha-amino acid combination in a metal ion ligand sphere. The synthesis and crystallization of these complexes was pH and concentration dependent, and their stability varied for different alpha-amino acids. X-ray structural studies of 1-3 have shown that the alpha-amino acids are coordinated as a zwitterion via one oxygen. This oxygen of the monodentate carboxylato group occupies an equatorial position in a distorted pentagonal bipyramid and encloses the pentagonal ring with the two bidentate peroxo groups. The apical positions are occupied by an oxo group and a water molecule, respectively. The Mo-O(O(2)) bonds are nonsymmetrical, differing in length by 0.009-0.045 Å. The longer bonds are located next to the coordinated carboxylato oxygen. A correlation between O-O and Mo-O bond lengths with the IR and UV-visible spectra of complexes 1-3 is discussed. Crystal structure of MoO(O(2))(2)(alanine)(H(2)O): monoclinic, space group P2(1)/c; Z = 4; a = 10.727(3) Å; b = 8.026(2) Å; c = 10.794(4) Å; beta = 110.81(2) degrees; V = 869 (Å)(3); R = 0.041. (1)H and (13)C NMR spectra in D(2)O solutions showed the presence of one complex species, which decomposed by standing in solution. Analogies and differences between Mo(VI) and V(V) peroxo complexes are outlined.

Journal Article↗
PubMed1971

N-(5'-phosphopyridoxyl)glutamic acid and N-(5'-phosphopyridoxyl)-2-oxopyrrolidine-5-carboxylic acid and their action on the apoenzyme of aspartate aminotransferase.

1. N-(5'-Phosphopyridoxyl)-l-glutamic acid (P-Pxy-Glu, compound I) is readily converted at pH3 into a substance (P-Pxy-Glp, compound II) characterized as N-(5'-phosphopyridoxyl)-2-oxopyrrolidine-5-carboxylic acid. 2. The u.v., i.r. and fluorescence spectra of P-Pxy-Glu and P-Pxy-Glp have been determined; from the u.v. spectra their pK values have been found and compared. 3. The apoenzyme of aspartate aminotransferase is rapidly and irreversibly inactivated by P-Pxy-Glu, but is inactivated more slowly by P-Pxy-Glp. The complex with P-Pxy-Glp is stable enough to be isolated, but it is slowly reactivated in the presence of excess of pyridoxal phosphate. 4. The u.v. spectrum of the complex of apoenzyme and P-Pxy-Glp suggests that it contains a hydrogen bond between the phenolic hydroxyl group and the pyrrolidone nitrogen; this specifies the conformation of most of the molecule of P-Pxy-Glp. This conformation is similar to that previously postulated for the enzyme-glutamate complex except for the side chain of glutamate. Hence both the affinity of P-Pxy-Glp for the apoenzyme and the fact that it is more easily removed than P-Pxy-Glu are explicable.

Aspartate Aminotransferases↗
PubMed1990

Increased expression of glutamic acid decarboxylase mRNA in rat substantia nigra after an ibotenic acid lesion in the caudate-putamen.

In situ hybridization histochemistry and RNA blots were used to study expression of glutamic acid decarboxylase (GAD) mRNA in rat caudate-nucleus and substantia nigra. In situ hybridization combined with computerized image analysis revealed that in the intact substantia nigra reticulata the cross-section area of GAD mRNA positive neurons were 25% larger in the dorsolateral part as compared with the ventromedial part. A unilateral ibotenic acid injection in caudate-putamen lesioned neurons, some of which project to the ipsilateral substantia nigra. An increased level of GAD mRNA was observed in substantia nigra ipsilateral to the lesion. Computerized image analysis of sections from in situ hybridization revealed an increase in the number of silver grains over GAD mRNA positive neurons in the dorsolateral substantia nigra reticulata ipsilateral to the lesion. However, no change was observed in the ventromedial part suggesting that GAD mRNA expression in this part of the nigra is less sensitive to inhibition by caudate-putamen afferents. In agreement with in situ experiments, RNA blots showed a 2-fold increased level of GAD mRNA in substantia nigra ipsilateral to the lesion. The increased GAD mRNA expression in the deafferented substantia nigra suggests a disinhibition of nigral GABA neurons, resulting in an increased utilization of GABA in these substantia nigra neurons.

Animals↗
PubMed1984

Vitamin-K-dependent carboxylation. Synthesis and biological properties of diastereoisomeric gamma-substituted glutamic acid containing peptidic substrates.

Pentapeptides Phe-Leu-X-Glu-Val where X is successively L-threo-gamma-fluoro-glutamyl, L-erythro-gamma-fluoro-glutamyl, L-threo-gamma-methyl-glutamyl or L-erythro-gamma-methyl-glutamyl have been synthesized and tested as substrates for the vitamin K-dependent carboxylation. L-threo- or L-erythro-gamma-methyl-glutamyl are not carboxylated but both corresponding peptides are inhibitors of the reaction. The L-threo-gamma-methyl-glutamyl containing peptide has the highest affinity described so far for the active site of the carboxylase (80 microM). In the gamma-fluoro-glutamyl series, only the L-erythro-gamma-fluoro-glutamyl residue is carboxylated, showing that the enzymatic hydrogen abstraction is stereospecific and corresponds to the elimination of the pro S hydrogen of glutamic acid. The lack of in vitro dicarboxylation of model peptides in contrast with the in vivo polycarboxylation of endogenous precursors is discussed along with the regiospecificity of the reaction with the different substrates.

Amino Acid Sequence↗
PubMed1986

Glutamic acid decarboxylase activity in micropunches of the deep cerebellar nuclei of the genetically dystonic (dt) rat.

Glutamic acid decarboxylase (GAD) activity was measured in specific divisions of the deep cerebellar nuclei of rats with an inherited dystonia. In 16-day-old dystonic rats there was a significant increase in GAD activity only in the nucleus interpositus (+26%). In 20-day-old dystonic rats GAD activity in all 3 cerebellar nuclei (fastigial, interpositus, dentate) was significantly increased compared to normal controls. The results indicate a spread of the anatomical locus of the neurochemical abnormality with time. During this period (postnatal days 16-20) there is a progressive worsening of the motor disorder in the affected animals.

Animals↗
PubMed2005

Synthesis and biological evaluation of N-[4-[5-(2,4-diamino-6-oxo-1,6-dihydropyrimidin-5-yl)-2-(2,2,2-trifluoroacetyl)pentyl]benzoyl]-L-glutamic acid as a potential inhibitor of GAR Tfase and the de novo purine biosynthetic pathway.

The synthesis and evaluation of N-[4-[5-(2,4-diamino-6-oxo-1,6-dihydropyrimidin-5-yl)-2-(2,2,2-trifluoroacetyl)pentyl]benzoyl]-L-glutamic acid (2) as an inhibitor of glycinamide ribonucleotide transformylase (GAR Tfase) and aminoimidazole carboxamide ribonucleotide transformylase (AICAR Tfase) are reported. The inhibitor 2 was prepared in a convergent synthesis involving C-alkylation of methyl 4-(4,4,4-trifluoro-3-dimethylhydrazonobutyl)benzoate with 1-chloro-3-iodopropane followed by construction of the pyrimidinone ring. Compound 2 was found to be an effective inhibitor of recombinant human GAR Tfase (K(i) = 0.50 microM), whereas it was inactive (K(i) > 100 microM) against E. coli GAR Tfase as well as recombinant human AICAR Tfase. Compound 2 exhibited modest, purine-sensitive growth inhibitory activity against the CCRF-CEM cell line (IC50 = 6.0 microM).

Antineoplastic Agents↗
PubMed1988

Types and distribution of glutamic acid decarboxylase (GAD)-immunoreactive neurons in mouse motor cortex.

Neuronal structures in mouse motor cortex that contain gamma-aminobutyric acid (GABA), were identified by an immunocytochemical method, using an antiserum to glutamic acid decarboxylase (GAD). GAD-positive cell bodies occurred in all layers of the motor cortex, but were more concentrated in layers III and VI. GAD-positive puncta, presumably axon terminals, were also distributed throughout the cortical layers; a high density of puncta occurred in layer III, whereas a somewhat lower density characterized layer VI. Based on the shapes of their somata and dendritic trees we concluded that all GAD-positive cells were of the non-pyramidal type.

Animals↗
PubMed2006

Co-localization of glutamic acid decarboxylase and phosphate-activated glutaminase in neurons of lateral reticular nucleus in feline thalamus.

Immunohistochemical methods were used to label singly and/or in combination glutamic acid decarboxylase (GAD, the sole synthesizing enzyme for the inhibitory neurotransmitter gamma-aminobutyric acid) and phosphate-activated glutaminase (GLN, a synthesizing enzyme for glutamate) in neurons of lateral reticular nucleus (LRN) of thalamus of adult cats. (1) GAD- and GLN-immunoreactivity (IR) exhibited matching regional patterns of organization within LRN. (2) GAD- and GLN-IR co-localized within most if not all LRN neuronal cell bodies as shown by light microscopy. (3) GAD- and GLN-IR had distinct subcellular localizations in LRN neurons as shown by correlative light/electron microscopy. LRN neurons are important conceptual models where strongly inhibitory cells receive predominant excitatory glutamatergic afferents (from neocortex). Consistent with known actions of intermediary astrocytes, LRN neurons demonstrate GLN enrichment synergistically coupled with glutamatergic innervation to supplement the glutamate pool for GABA synthesis (via GAD) and for metabolic utilization (via the GABA shunt/tricarboxylic acid cycle) but not, apparently, for excitatory neurotransmission.

Animals↗