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At least 253 records · Page 14Linked to original sources
PubMed1980

Effects of 3,4-dihydroxyphenylpyruvic acid and L-glutamic acid on some pharmacokinetic parameters of L-dopa in the rat.

In the rat, various oral doses of 3,4-dihydroxyphenylpyruvic acid (DHPPA) administered simultaneously with L-dopa were shown to elevate the serum L-dopa and cerebral dopamine concentrations dose-dependently. With increasing DHPPA: L-dopa ratio the L-dopa-sparing effect became greater. Although oral and intravenous doses of DHPPA showed that it was readily converted to L-dopa in the serum, only small amounts of dopamine (DA) were detected in the brain. The high 3-O-methyldopa concentrations, measured in the serum after DHPPA administration, might be responsible for the failure of the L-dopa formed to pass the blood-brain barrier. Concomitant administration of L-dopa and glutamic acid gave significantly higher L-dopa values in the serum and DA and homovanillic acid values in the brain than did the same dose of L-dopa alone. This indicates that the transamination of L-dopa can also be effected by coadministration of L-dopa and an amino group donor in vivo.

Animals↗
PubMed1999

Conformationally Constrained 7-Azabicyclo[2.2.1]heptane Amino Acids. Synthesis of a Glutamic Acid Analogue.

We report the synthesis of 2-substituted 7-azabicyclo[2.2.1]heptane glutamic acid analogue 27 from L-serine. Hemiaminal intermediate 2 can be converted to the 2S,3S,5S-trisubstituted pyrrolidine 3 by a tandem Wittig/Michael reaction or to the 2S,3S,5R-trisubstituted pyrrolidine 4 via an iodosulfonamidation reaction. The key transannular alkylation step to form the [2.2.1] ring system involves a beta-elimination of a silyl ether followed by cyclization to afford tert-butyl 7-benzyloxycarbonyl-7-azabicyclo[2.2.1]-2-heptene-1-carboxylate (20). Selective functionalization at C-2 was accomplished by the direct reduction with SmI(2) of 2-keto-3-silyl ether 23 to the C-2 ketone 24, which was converted to alpha,beta-unsaturated ester 25. Stereospecific reduction of the double bond from the exo face leads to a single protected glutamate analogue, tert-butyl (1S,2R,4R)-7-benzyloxycarbonyl-2-(methoxycarbonylmethyl)-7-azabicyclo[2.2.1]heptane-1-carboxylate (27).

Journal Article↗
PubMed2003

Rational design, synthesis, and pharmacological evaluation of 2-azanorbornane-3-exo,5-endo-dicarboxylic acid: a novel conformationally restricted glutamic acid analogue.

The design and synthesis of conformationally restricted analogues of alpha-amino acids is an often used strategy in medicinal chemistry research. Here we present the rational design, synthesis, and pharmacological evaluation of 2-azanorbornane-3-exo,5-endo-dicarboxylic acid (1), a novel conformationally restricted (S)-glutamic acid (Glu) analogue intended as a mimic of the folded Glu conformation. The synthesis of 1 was completed in its racemic form in eight steps from commercially available starting materials. As a key step, the first facially selective hydroboration of a 5-methylidene[2.2.1]bicyclic intermediate was investigated. In this transformation, the catalytic methodology of Wilkinson's/catechol borane proved superior to stoichiometric borane or dialkyl borane reagents, in terms of higher diastereomeric excess and chemical yield. To our surprise (+/-)-1 did not show affinity in binding studies on native 2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) (IC(50) > 300 microM, [(3)H]AMPA) or kainic acid (IC(50) > 160 microM, [(3)H]kainic acid) receptors nor in binding studies on the cloned iGluR5,6 subtypes (IC(50) > 300 microM, [(3)H]kainic acid).

Aza Compounds↗
PubMed1988

The same substitution, glutamic acid----lysine at position 501, occurs in three alloalbumins of Asiatic origin: albumins Vancouver, Birmingham, and Adana.

A strategy is described for identifying structural changes in genetic variants of human serum albumin (alloalbumins). By use of this strategy we have determined an amino acid substitution in three alloalbumins of Asiatic origin. The same amino acid exchange, glutamic acid----lysine at position 501, occurs in albumins Vancouver and Birmingham, both from families that migrated from northern India, and also in albumin Adana from Turkey. This exchange corresponds to a single base mutation in the codon GAG to AAG and accords with the slow mobility of the three albumins at pH 8.6. Each of the three alloalbumins had been reported to be a new variant, yet they have the same substitution. These results emphasize the need for structural study of genetic variants that have been differentiated only by nonspecific physical criteria such as dye binding and electrophoretic mobility. We know of no other description of the substitution involved in an alloalbumin originating from the Indian subcontinent. However, the same change of glutamic acid----lysine at position 501 may be present in several other named variants reported for populations in north India and the surrounding regions.

Amino Acid Sequence↗
PubMed1985

Neurons and terminals in the retrohippocampal region in the rat's brain identified by anti-gamma-aminobutyric acid and anti-glutamic acid decarboxylase immunocytochemistry.

The distribution of gamma-aminobutyric acid (GABA) containing nerve cells and terminals was studied at the light and electron microscopic levels in the retrohippocampal region of the rat by using anti-glutamic acid decarboxylase (GAD) and anti-GABA antibodies in immunocytochemistry. Large numbers of GAD and GABA stained cells were found in all retrohippocampal structures. At the ultrastructural level, the immunoreactivity against GABA and against the synthesizing enzyme GAD was localized to cytoplasmic structures, including loose clumps of rough endoplasmic reticulum, ribosomal arrays, outer mitochondrial surfaces and in axonal boutons. The GAD- and GABA-immunoreactive(-i) cells were found in all subfields of the retrohippocampal region (e.g., the subicular complex, the entorhinal area). Within the entorhinal area a slightly larger number of immunoreactive cells could be detected in layers II and III than in the other layers. In the subiculum, pre- and parasubiculum the GAD and GABA-i cells were present in relatively large numbers in all layers, except the molecular layer, which contained only a small number of GABA cells. Within the entorhinal area, GAD and GABA stained cells ranged in size from small (13 micron in diameter) to large (22 micron in diameter). A large number of different morphological classes of cells were found, except pyramidal and stellate cells. In the pre- and parasubiculum, on the other hand, the GABA cells were generally small to medium in size and morphologically more homogeneous than in the subiculum and entorhinal area. The entire retrohippocampal region was densely innervated by GABA preterminal processes, with little variation in the regional density of innervation. Within the entorhinal area, presubiculum and subiculum, a clear difference was found in the laminar pattern of innervation. In all three subfields the densest innervation was in layer II. In the entorhinal area both GAD- and GABA-i axons form palisades of fibers around the somata of neurons, which are tightly packed together in this layer. In the electron microscope both GAD-i and GABA-i were demonstrated in these axons. Axosomatic synaptic contacts were common between axons and the stellate neurons and other cells of this layer. Layers IV and VI appeared less dense in GAD-i terminals but appeared more densely innervated than layers III and V. The lamina dessicans was relatively poor in GAD-i. In the subiculum and presubiculum, as well as all other subfields of the hippocampal region, the innervation is dominated by axo-somatic innervation of layer II cells.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1997

Conformational analysis of glutamic acid analogues as probes of glutamate receptors using molecular modelling and NMR methods. Comparison with specific agonists.

The activity of five glutamic acid analogues substituted in position 3 or 4 by a methyl (3T, 3E, 4T, and 4E) or a methylene group (4M) has been examined at one cloned Glu receptor subtype, mGluR1. These analogues interact with glutamate receptors of the central nervous system, especially the ligand 4T [(2S,4S)-4-methylglutamic acid] at the metabotropic glutamate receptor mGluR1. It was observed that only the 4T isomer is as potent an agonist as glutamic acid, whereas other isomers are less active. Furthermore, 4E [(2S,4R)-4-methylglutamic acid] exhibited an exceptional selectivity for the KA ionotropic receptor subtype while 4M [(2S)-4-methyleneglutamic acid] was active at the NMDA receptors. These molecules represent suitable tools among a population of similar glutamate analogues for a classical structure-function relationship study. We have undertaken a conformational analysis by 1H and 13C NMR spectroscopy and molecular modelling of these molecules. Hetero- and homonuclear coupling constants were measured in order to assign the diastereotopic methylene protons at C(3) or C(4), and used for comparison in molecular dynamics (MD) simulations. The hydrogen-bonding possibility, steric effects or electrostatic interactions may be a considerable influence in stabilizing a conformational population in D2O solution. The conformations may be grouped by the two backbone torsion angles, chi 1 [alpha-CO2(-)-C(2)-C(3)-C(4)] and chi 2 [+NC(2)-C(3)-C(4)-gamma CO2-] and by the two characteristic distances between the potentially active functional groups, alpha N(+)-gamma CO2- (d1) and alpha CO2(-)-gamma CO2- (d2). The conformational preferences in solution of 4T, 4E and (3T, 3E, 4M) are discussed in the light of the physical features known for a specific metabotropic agonist (ACPD) and specific ionotropic agonists (KA) and (NMDA), respectively.

Animals↗
PubMed1993

Inhibition of aminopeptidases by phosphonic acid and phosphinic acid analogues of aspartic and glutamic acids.

More than 30 phosphonic and phosphinic acid analogues of aspartic and glutamic acids were synthesized in order to probe how the structural differences of these molecules were reflected in their ability to inhibit cytosolic (LAP) and microsomal (APM) aminopeptidases. Although most of the compounds studied were found to exert only a modest inhibitory effect, the studies provide some information on the structural requirements of the binding subsites and catalytic centers of both enzymes.

Aminopeptidases↗
PubMed1994

Site-directed mutagenesis of the catalytic base glutamic acid 400 in glucoamylase from Aspergillus niger and of tyrosine 48 and glutamine 401, both hydrogen-bonded to the gamma-carboxylate group of glutamic acid 400.

Replacement of the catalytic base Glu400 by glutamine in glucoamylase from Aspergillus niger affects both substrates ground-state binding and transition-state stabilization. Compared to those of the wild-type enzyme, Km values for maltose and maltoheptaose are 12- and 3-fold higher for the Glu400-->Gln mutant, with kcat values 35- and 60-fold lower, respectively, for the same substrates. This unusually high residual activity for a glycosylase mutant at a putative catalytic group is tentatively explained by a reorganization of the hydrogen bond network, using the crystal structure of the related Aspergillus awamori var. X100 glucoamylase in complex with 1-deoxynojirimycin [Harris, E. M. S., Aleshin, A. E., Firsov, L. M., & Honzatko, R. B. (1993) Biochemistry 32, 1618-1626]. Supposedly Gln400 in the mutant hydrogen bonds to the invariant Tyr48, as does Glu400 in the wild-type enzyme. For Tyr48-->Trp A. niger glucoamylase kcat is reduced 80-100-fold, while Km is increased only 2-3-fold. Gln401 also hydrogen bonds to Glu400, but its mutation to glutamic acid has only a minor effect on activity. The Tyr48-->Trp and Glu400-->Gln glucoamylases share particular features in displaying unusually high activity below pH 4.0-which reflects lack of the wild-type catalytic base function- and unusually low binding affinity at subsite 2. Both mutants have lost 13-16 kJ mol-1 in transition-state stabilization energy.(ABSTRACT TRUNCATED AT 250 WORDS)

Aspergillus niger↗
PubMed1975

Biosynthesis of delta-aminolevulinic acid from the intact carbon skeleton of glutamic acid in greening barley.

The customary route in animals and bacteria for delta-aminolevulinic acid biosynthesis is from glycine and succinyl CoA, catalyzed by the enzyme delta-aminolevulinic acid synthetase [succinyl-CoA:glycine C-succinyltransferase (decarboxylating), EC 2.3.1.37]. Attempts to demonstrate this route in plants have been unsuccessful. Evidence is given for a new enzymic route of synthesis of delta-aminolevulinic acid in plants. This route involves the incorporation of the intact five-carbon skeleton of glutamic acid into delta-aminolevulinic acid. Demonstration of the new pathway in plants has been made by feeding specifically labeled [14C]glutamic acid to etiolated barley shoots greening in the light. In the presence of levulinate, a competitive inhibitor of delta-aminolevulinic acid dehydrastase [porphobilinogen synthase; delta-aminolevulinate hydro-lyase (adding delta-aminolevulinate and cyclizing); EC 4.2.1.24], delta-aminolevulinate accumulates. The delta-aminolevulinate formed was chemically degraded by periodate to formaldehyde and succinic acid. The C5 (formaldehyde) fragment was separated, as the 5,5-dimethyl-1,3-cyclohexanedione (dimedone) derivative, from the C1-C4 (succinic acid) fragment. The C5 atom contained radioactivity predominantly derived from C1 of glutamic acid. Conversely, the labeled C3 and C4 atoms of glutamic acid were found primarily in the succinic acid (C1-C4) fragment of delta-aminolevulinate. This labeling pattern for delta-aminolevulinic acid is consistent with a biosynthetic route utilizing the intact five-carbon skeleton of alpha-ketoglutarate, glutamate, or glutamine, and is inconsistent with the delta-aminolevulinic acid synthetase pathway utilizing glycine and succinyl CoA as precursors.

Aminolevulinic Acid↗
PubMed1994

Effect of various analogues of D-glutamic acid on the D-glutamate-adding enzyme from Escherichia coli.

Twenty-four analogues of D-glutamic acid were tested as substrates or inhibitors of the D-glutamate-adding enzyme from Escherichia coli. The best substrates were, in decreasing order of specific activity, D-erythro-4-methylglutamic acid, D-erythro-3-methylglutamic acid, DL-homocysteic acid, (+/-)-trans-1-amino-3-carboxy-cyclopentanecarboxylic acid and (+/-)-trans-1-amino-3-carboxy-cyclohexanecarboxylic acid. Among the different stereoisomers, only the D-erythro isomers for methylglutamic acids, and the trans isomers for the cyclic analogs, were substrates. Apart from the D-erythro-3- and 4-methylglutamic acids and DL-homocysteic acid, none of the examined compounds significantly inhibited the addition of radioactive D-glutamic acid to UDP-N-acetylmuramyl-L-alanine.

Escherichia coli↗
PubMed1987

High-affinity transport of gamma-aminobutyric acid, glycine, taurine, L-aspartic acid, and L-glutamic acid in synaptosomal (P2) tissue: a kinetic and substrate specificity analysis.

In a cortical P2 fraction, [14C]gamma-aminobutyric acid ([14C]GABA), [14C]glycine, [14C]taurine, and [14C]glutamic and [14C]aspartic acids are transported by four separate high-affinity transport systems with L-glutamic acid and L-aspartic acid transported by a common system. GABA transport in cortical synaptosomal tissue occurs by one high-affinity system, with no second, low-affinity, transport system detectable. Only one high-affinity system is observed for the transport of aspartic/glutamic acids; as with GABA transport, no low-affinity transport is detectable. In the uptake of taurine and glycine (cerebral cortex and pons-medulla-spinal cord) both high- and low-affinity transport processes could be detected. The high-affinity GABA and high-affinity taurine transport classes exhibit some overlap, with the GABA transport system being more specific and having a much higher Vmax value. High-affinity GABA transport exhibits no overlap with either the high-affinity glycine or the high-affinity aspartic/glutamic acid transport class, and in fact they demonstrate somewhat negative correlations in inhibition profiles. The inhibition profiles of high-affinity cortical glycine transport and those of high-affinity cortical taurine and aspartic/glutamic acid transport also show no significant positive relationship. The inhibition profiles of high-affinity glycine transport in the cerebral cortex and in the pons-medulla-spinal cord show a significant positive correlation with each other; however, high-affinity glycine uptake in the pons-medulla-spinal cord is more specific than that in the cerebral cortex. The inhibition profile of high-affinity taurine transport exhibits a nonsignificant negative correlation with that of the aspartic/glutamic acid transport class.

Amino Acids↗