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PubMed1979

The antagonizing effect of aspartic acid on morphine withdrawal and levallorphan-precipitated abstinence syndrome signs and on associated changes in brain levels of free amino acids in the rat.

We have previously demonstrated the antagonizing effect of aspartic acid on some effects of morphine and on the development of physical dependence on, and tolerance to, morphine. In the present study, we have withdrawal from morphine or administration of a morphine antagonist. For this purpose sixty five white rats were given morphine and aspartic acid separately and in combination in a 5% saccharose solution instead of drinking water for 30 days. Some of the dependent rats were then withdrawn and others were injected with levallorphan. Flying, jumping, wet-dog shaking, body weight loss and motor activity were estimated and free amino acid levels in the brain were determined. Aspartic acid was found to prevent or antagonize the behavioural signs and the changes in the free amino acid levels in the brain. The results are discussed in the light of the previous data.

Amino Acids↗
PubMed1982

Covalent attachment of aspartic acid to yeast aspartyl-tRNA synthetase induced by the enzyme.

Aspartic acid can be covalently linked to yeast aspartyl-tRNA synthetase and to other proteins, in the absence of tRNA, under conditions where the synthetase activates the amino acid into aspartyl-adenylate, i.e., in the presence of ATP and MgCl2. The linkage between aspartic acid and the protein is acid and alkali resistant; thus it is likely a peptide-like amide bond formed between the activated carboxylate group of aspartic acid and the primary amine function of the side chain of lysine residues.

Amino Acids↗
PubMed2000

Effect of self-etching primers containing N-acryloyl aspartic acid on dentin adhesion.

The purpose of this study was to evaluate the feasibility of aspartic acid derivative, N-acryloyl aspartic acid (N-AAsp) when used as a self-etching primer prior to the application of a commercial bonding agent containing 10-methacryloxydecyl dihydrogen phosphate. N-AAsp was synthesized by the reaction of DL-aspartic acid and acryloyl chloride. N-AAsp can be dissolved in water up to 25 wt % and can adequately remove the smear layer. When 20 wt % N-AAsp was applied as a self-etching primer, the tensile bonding strength of resin composite to dentin doubled to 16.0 MPa compared with that of the nonetching group or the 40 wt % H(3)PO(4) etching/water rinse group. Scanning electron microscopic observations revealed that the formation of the hybrid layer at the interface between the resin composite and dentin and the thickness of the hybrid layer increased with N-AAsp concentration. The hybrid layer in the specimens treated with 20 wt % N-AAsp aqueous solution presented a uniform structure, whereas those treated with 5 wt % N-AAsp solution showed a porous structure. We conclude that 20 wt % N-AAsp aqueous solution has good potential value as a self-etching primer.

Acid Etching, Dental↗
PubMed1995

The catalytic role of aspartic acid-92 in a human dual-specific protein-tyrosine-phosphatase.

The mechanism of catalysis for the human dual-specific (vaccinia H1-related) protein-tyrosine-phosphatase was investigated. The pH dependence of the kcat value is bell-shaped when p-nitrophenyl phosphate was employed as a model substrate. The kcat/Km pH profile rises with a slope of 2 and decreases with a slope of -1, indicating that two groups must be unprotonated and one group must be protonated for activity. An amino acid residue with an apparent pKa value of 5.5 +/- 0.2 must be unprotonated and a residue with a pKa value of 5.7 must be unprotonated for activity. The pKa value of the catalytic cysteine-124 (C124) was 5.6 +/- 0.1. The aspartic acid-92-asparagine (D92N) mutant enzyme was 100-fold less active than the native enzyme and exhibited the loss of the basic limb in the pH profiles, suggesting that in the native enzyme D92 must be protonated for activity. The D92 residue is conserved throughout the entire family of dual-specific phosphatases. Mutants glutamic acid-6-glutamine, glutamic acid-32-glutamine, aspartic acid-14-asparagine, and aspartic acid-110-asparagine had less than a 2-fold effect on the kinetic parameters when compared to native enzyme. Based upon the lack of a "burst" in rapid reaction kinetics, formation of the intermediate is rate-limiting with both native and D92N mutant enzymes. In agreement with rate-limiting formation of the intermediate, the pKa value of 5.5 for the group which must be unprotonated for activity was assigned to C124.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1992

N-methyl-D-aspartic acid (NMDA) and non-NMDA receptors regulating hippocampal norepinephrine release. I. Location on axon terminals and pharmacological characterization.

UNLABELLED: The effects of endogenous and exogenous agonists at excitatory amino acid receptors mediating enhancement of [3H]norepinephrine [( 3H]NE) release have been investigated using superfused rat hippocampal synaptosomes. In Mg(++)-free medium L-glutamic acid (L-Glu), L-aspartic acid (L-Asp), N-methyl-D-aspartic acid (NMDA), kainic acid, (RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and quisqualic acid (QA) all increased the release of [3H]NE. L-Glu produced the largest effect. In the presence of Mg++ (1.2 mM), the effect of L-Glu decreased by about 40%; L-Asp and NMDA lost completely their activity while the effects of kainic acid, QA and AMPA did not change significantly. Similarly to NMDA, the effect of L-Asp was augmented by glycine and blocked by NMDA receptor antagonists, while it was insensitive to the non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). The effect of L-Glu on [3H] NE release was partly decreased by the NMDA receptor channel blocker (+)-5-methyl-10,11-dihydro-5-H-dibenzo[a,d]cycloepten-5,10-imine (MK-801) and partly by CNQX; when present together, the two antagonists completely abolished the L-Glu effect. The QA enhancement of [3H]NE release was antagonized by CNQX but it was insensitive to other classical non-NMDA receptor antagonists. IN CONCLUSION: 1) release-enhancing NMDA and non-NMDA receptors exist on noradrenergic axon terminals of rat hippocampus; 2) L-Asp appears to be a potent selective NMDA receptor agonist while L-Glu can activate also non-NMDA receptors; 3) the NE-releasing receptor activated by QA may represent a QA/AMPA receptor subtype.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed1974

Chemical conversion of aspartic acid 52, a catalytic residue in hen egg-white lysozyme, to homoserine.

Hen egg-white lysozyme (EC 3.2.1.17) was specifically esterified at aspartic acid 52 by the affinity labeling reagent 2',3'-epoxypropyl beta-glycoside of di-(N-acetyl-D-glucosamine) [Eshdat et al. (1973) J. Biol. Chem.248, 5892]. The disulfide bonds of the affinity-labeled enzyme and the aspartic acid 52-ester bond were reduced with dithiothreitol and sodium borohydride, respectively, resulting in the removal of the affinity label. The reduced protein contained 0.9 mole of homoserine and 1 mole less of aspartic acid per mole of protein, as compared to the native enzyme. It was reoxidized by a mixture of reduced and oxidized glutathione to yield a modified protein that possessed one-tenth of the activity of native lysozyme (presumably due to a contamination by regenerated lysozyme formed as a result of hydrolysis of the aspartic acid 52-ester bond during the chemical treatment). The native enzyme, after reduction and reoxidation in the same manner, retained its amino-acid composition, full enzymatic activity, and fluorescence properties. The modified lysozyme, containing homoserine 52, showed the same fluorescence spectrum as the native enzyme. With both proteins, the fluorescence maximum shifted to the blue to a similar extent upon the addition of the saccharide inhibitors tri-(N-acetyl-D-glucosamine) and the cell-wall tetrasaccharide (GlcNAc-MurNAc)(2). The modified enzyme bound these two saccharides with nearly the same binding constants as those found for native lysozyme and for lysozyme that was reduced and reoxidized. Since the side chain of homoserine is similar in size to that of aspartic acid, it is concluded that the loss of enzymatic activity is the direct result of the chemical modification of the carboxyl side chain of aspartic acid 52, thus showing that this amino acid is essential for the catalytic action of the enzyme.

Amino Acid Sequence↗
PubMed1988

Application to forensic odontology of aspartic acid racemization in unerupted and supernumerary teeth.

Racemization of aspartic acid in dentin protein during the human lifetime progresses with age. The extent of racemization of aspartic acid in coronal dentin of normal permanent teeth can be used in forensic odontology to estimate the age of an individual at the time of death (Ogino et al., 1985). A series of experiments was conducted with dentin separated from unerupted and supernumerary teeth of various ages in an attempt to evaluate the advantages and limitations of this age-estimation method. The current study on nine tooth specimens showed that some unerupted permanent teeth with normal-sized and -shaped crowns (impacted third molar, canine, and incisor) could be used to estimate the age of individuals at the time of death within +/- 4 years. However, supernumerary teeth (mesiodens, paramolar) with extremely tiny (length of crown: 4 approximately 5 mn) and abnormally shaped crowns could not be used for analysis. In such cases, the estimated age of individuals analyzed by the racemization method deviated considerably from their actual age.

Adolescent↗
PubMed1988

Aspartic acid aminotransferase activity is increased in actively spiking compared with non-spiking human epileptic cortex.

Increased concentration of the excitatory neurotransmitter aspartic acid in actively spiking human epileptic cerebral cortex was recently described. In order to further characterise changes in the aspartergic system in epileptic brain, the behaviour of aspartic acid aminotransferase (AAT), a key enzyme involved in aspartic acid metabolism has now been examined. Electrocorticography performed during surgery was employed to identify cortical epileptic spike foci in 16 patients undergoing temporal lobectomy for intractable seizures. Patients with spontaneously spiking lateral temporal cortex (n = 8) were compared with a non-spiking control group (n = 8) of patients in whom the epileptic lesions were confined to the hippocampus sparing the temporal convexity. Mean activity of AAT in spiking cortex was significantly elevated by 16-18%, with aspartic acid concentration increased by 28%. Possible explanations for the enhanced AAT activity include increased proliferation of cortical AAT-containing astrocytes at the spiking focus and/or a generalised increase in neuronal or extraneuronal metabolism consequent to the ongoing epileptic discharge. It is suggested that the data provide additional support for a disturbance of central excitatory aspartic acid mechanisms in human epileptic brain.

Adolescent↗
PubMed1984

A multinuclear NMR relaxation study of the interaction of divalent metal ions with L-aspartic acid.

Carbon-13 spin-lattice relaxation times, T1, have been measured for aqueous solutions of L-aspartic acid, L-alanine, O-phospho-L-serine, and 2-mercapto-L-succinic acid in the presence of the paramagnetic metal ions, Cu2+ and Mn2+, and Mg2+ as a diamagnetic control, at ambient temperature and neutral pH. Nitrogen-15, oxygen-17 and proton relaxation times were also obtained for L-aspartic acid and phosphorus-31 relaxation times for O-phospho-L-serine under similar conditions. The structures of these complexes in solution were determined from the various metal ion-nuclei distances calculated from the paramagnetically-induced relaxation. These results indicate that the Cu2+ interaction with L-aspartic acid is through alpha-amino and beta-carboxyl groups while Mn2+ coordinates most strongly through alpha- and beta-carboxyl groups, with the possibility of a weak interaction through the amino group. An examination of the coordination of these divalent metal ions to an analog of L-aspartic acid in which the beta-carboxyl group is replaced by a phosphate group (O-phospho-L-serine) indicated that Cu2+ coordination is now probably through the alpha-amino and phosphate groups, while this analog is a monodentate ligand for Mn2+ coordinating through the phosphate group. Removal of the beta-carboxyl group (L-alanine) also results in Cu2+ coordination through the alpha-carboxyl and alpha-amino groups, and the same ligand interactions are observed with Mn2+. Replacement of the alpha-amino group of L-aspartic acid with an -SH group (2-mercapto-L-succinate) is sufficient to eliminate any specific coordination with either Cu2+ or Mn2+.

Alanine↗
PubMed1979

The effect of postirradiation application of aspartic acid salts on hemopoietic recovery in sublethally X-irradiated mice.

The effect of aspartic acid salts, especially of K and Mg aspartates, on certain hematological changes in the peripheral blood and hemopoietic organs of sublethally X-irradiated male mice of the strain C57Bl/10 was investigated. Salts of aspartic acid were administered in tap water after irradiation. A favorable effect of aspartic acid salts on erythropoietic recovery and on regeneration of thymus weight was found during the first two weeks after irradiation.

Animals↗
PubMed1991

Conversion of citrate synthase into citryl-CoA lyase as a result of mutation of the active-site aspartic acid residue to glutamic acid.

The active-site aspartic acid residue, Asp-362, of Escherichia coli citrate synthase was changed by site-directed mutagenesis to Glu-362, Asn-362 or Gly-362. Only very low catalytic activity could be detected with the Asp----Asn and Asp----Gly mutations. The Asp----Glu mutation produced an enzyme that expressed about 0.8% of the overall catalytic rate, and the hydrolysis step in the reaction, monitored as citryl-CoA hydrolysis, was inhibited to a similar extent. However, the condensation reaction, measured in the reverse direction as citryl-CoA cleavage to oxaloacetate and acetyl-CoA, was not affected by the mutation, and this citryl-CoA lyase activity was the major catalytic activity of the mutant enzyme. This high condensation activity in an enzyme in which the subsequent hydrolysis step was about 98% inhibited permitted considerable exchange of the methyl protons of acetyl-CoA during catalysis by the mutant enzyme. The Km for oxaloacetate was not significantly altered in the D362E mutant enzyme, whereas the Km for acetyl-CoA was about 5 times lower. A mechanism is proposed in which Asp-362 is involved in the hydrolysis reaction of this enzyme, and not as a base in the deprotonation of acetyl-CoA as recently suggested by others. [Karpusas, Branchaud & Remington (1990) Biochemistry 29, 2213-2219; Alter, Casazza, Zhi, Nemeth, Srere & Evans, (1990) Biochemistry 29, 7557-7563].

Acetyl Coenzyme A↗
PubMed2000

Differentiating alpha- and beta-aspartic acids by electrospray ionization and low-energy tandem mass spectrometry.

Spectra obtained by low-energy electrospray ionization tandem mass spectrometry (ESI-MS/MS) of 34 peptides containing aspartic acids at position n were studied and unambiguously differentiated. beta-Aspartic acid yields an internal rearrangement similar to that of the C-terminal rearrangements of protonated and cationized peptides. As a result of this rearrangement, two different ions containing the N- and the C-terminal ends of the original peptide are formed, namely, the bn-1 + H2O and y"l - n + 1 - 46 ions, respectively, where e is the number of amino acid residues in the peptide. The structure suggested for the y"l - n + 1 - 46 ion is identical to that proposed for the vn ions observed upon high-energy collision-induced dissociation (CID) experiments. The intensity of these ions in the low-energy MS/MS spectra is greatly influenced by the presence and position of basic amino acids within the sequences. Peptides with a basic amino acid residue at position n - 1 with respect to the beta-aspartic acid yield very intense bn-1 + H2O ions, while the y"l - n + 1 - 46 ion was observed mostly in tryptic peptides. Comparison between the high- and low-energy MS/MS spectra of several isopeptides suggests that a metastable fragmentation process is the main contributor to this rearrangement, whereas for long peptides (40 AA) CID plays a more important role. We also found that alpha-aspartic acid containing peptides yield the normal immonium ion at 88 Da, while peptides containing beta-aspartic acid yield an ion at m/z 70, and a mechanism to explain this phenomenon is proposed. Derivatizing isopeptides to form quaternary amines, and performing MS/MS on the sodium adducts of isopeptides, both improve the relative intensity of the bn + 1 + H2O ions. Based on the above findings, it was possible to determine the isomerization sites of two aged recombinant growth proteins.

Amino Acid Sequence↗
PubMed1994

2,4-Dimethyl-5(4H)-oxazolone as reagent for activation and coupling of N-substituted aspartic acid.

Reaction of the title oxazolone with N-benzyloxycarbonyl-L-aspartic acid in dichloromethane followed by addition of phenylalanine methyl ester.HCl and N-methylmorpholine gave a 90% yield of a mixture of alpha- and beta-isomers of Z-aspartylphenylalanine methyl esters in a 7:3 ratio. Reaction of the oxazolone with N-acetyl-L-aspartic acid anhydride gave a 75% yield of crystalline N-acetyl-L-aspartic acid anhydride. tert-Butoxycarbonylaspartic and Z-glutamic acids also underwent activation to give the anhydrides.

Aspartic Acid↗
PubMed1986

Interaction between L-aspartic acid and L-asparaginase from Escherichia coli: binding and inhibition studies.

Experiments using equilibrium dialysis and fluorescence quenching provided direct evidence that approximately four moles of L-aspartic acid were bound per mole of tetrameric L-asparaginase from Escherichia coli, with a dissociation constant on the order of 60-160 microM. In addition, a set of weaker binding sites with a dissociation constant in the millimolar range were detected. Kinetic studies also revealed that L-aspartic acid inhibited L-asparaginase competitively, with an inhibition constant of 80 microM at micromolar concentrations of L-asparagine; at millimolar concentrations of the amide, an increase in maximal velocity but a decrease in affinity for L-asparagine were observed. L-Aspartic acid at millimolar levels again displayed competitive inhibition. These and other observations suggest that L-aspartic acid binds not only to the active site but also a second site with lower intrinsic affinity for it. The observed "substrate activation" is most likely attributable to the binding of a second molecule of L-asparagine rather than negative cooperativity among the tight sites of the subunits of this tetrameric enzyme. Further support for L-aspartic acid binding to the active site comes from experiments in which the enzyme, when exposed to various group-specific reagents suffered parallel loss of catalytic activity and in its ability to bind L-aspartic acid. Different commercial preparations of Escherichia coli L-asparaginase were found to contain approximately 2-4 moles of L-aspartic acid; these were incompletely removed by dialysis, but could be removed by transamination or decarboxylation. Efficiency of dialysis increased with increasing pH. Taken together, this set of results is consistent with the existence of a covalent beta-aspartyl enzyme intermediate.

Asparaginase↗
PubMed1994

A phase I-II study of N-(phosphonacetyl)-L-aspartic acid (PALA) added to 5-fluorouracil and folinic acid in advanced colorectal cancer.

N-(phosphonacetyl)-L-aspartic acid (PALA) inhibits the enzyme L-aspartic acid transcarbamoylase (ATCase) which is important in de novo pyrimidine synthesis. Low dosages of PALA modulate the in vitro activity of 5-fluorouracil (5-FU) and PALA (250 mg/m2) inhibits pyrimidine synthesis in patients. PALA (250 mg/m2 day 1) was combined with an established 5-FU/folinic acid (FA) regimen [FA (200 mg/m2 over 2 h days 2 + 3) and bolus and 22 h infusional 5-FU (300-500 mg/m2 days 2 + 3)] without the need for dose reduction of 5-FU or FA. 35 patients were entered. Treatment was well tolerated; 4/27 patients experienced > or = ECOG grade 3 toxicity at full 5-FU dosage (500 mg/m2 bolus/infusion). However, the response rate in 33 evaluable patients was only 6.1% [95% confidence intervals (C.I.) 0.2-21.8%]. Median response duration was short (4 months, 95% C.I. 3-6 months) and overall median survival was 10 months (95% C.I. 7-16 months). Although PALA (250 mg/m2) can be combined with full dosage 5-FU/FA, the combination has poor activity in colorectal cancer.

Adolescent↗
PubMed1980

Cytostatic activity in vitro of cycloleucine, aspartic acid and glutamic acid phosphonic analogues.

Cytostatic activity of 18 new phosphonic acid derivatives of cycloleucine, aspartic acid and glutamic acid was tested against human KB and mouse L1210s leukemia cell lines in vitro. The tests were performed according to international protocol 1.600 for screening of chemical agents against tissue culture system. Four of the tested compounds revealed their cytostatic activity at the dose 10 micrograms/ml.

Amino Acids↗
PubMed2004

Mass spectrometric differentiation of alpha- and beta-aspartic acid in a pseudo-tetrapeptide thrombosis inhibitor and its isomer.

The pseudo-tetrapeptide designated here as RGD (N-ethyl-N-[1-oxo-4-(4-piperidinyl) butyl] glycyl-L-alpha- aspartyl-3-cyclohexyl-L-alaninamide) and its isomer with beta-aspartic acid rather than alpha-aspartic acid were examined using electrospray ionization (ESI) and Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR-MS). RGD has potential as a thrombosis inhibitor and the isomer, designated here as isopeptide, is an inactive instability product; hence, means were sought to distinguish the two. Both isomers give a protonated parent on ESI and fragments typical of peptides on sustained off resonance irradiation collision-induced decomposition (SORI-CID). Cleavage at the aspartic acid (b(3)) is the dominant process in both isomers, although a significant b(2) and smaller a(2)" and c(2)" peaks are also observed. More distinctive are peaks observed at b(3)-H(2)O, b(3)-(CO + CO(2)) and, only in the case of the RGD, b(3) - (H(2)O + CO). SORI CID on the b(3) ion indicates that, of these distinctive peaks, only the b(3)-(CO + CO(2)) comes from decomposition of the b(3) ion. On this basis, a mechanism is suggested for b(3) formation, involving proton transfer from a back-bone carbonyl to the aspartic acid side-chain carboxyl group. Such an intramolecular proton transfer involves rings of different sizes for the two isomers, providing a basis for the different SORI energy dependences. A mechanism suggested for the formation of the b(3)-H(2)O fragments also involves proton transfer to the aspartic acid side chain carboxyl group. This leads to concomitant H(2)O loss and amide bond cleavage, giving the b(3)-H(2)O ions with ketene moieties resulting from the water loss. According to the suggested mechanism, the observed loss of CO (verified by SORI-CID on the b(3)- H(2)O ion) from the RGD b(3)-H(2)O peak results in a secondary carbocation stabilized by an adjacent nitrogen. The unobserved loss of CO from the b(3)-H(2)O ion, formed by the suggested mechanism from the isopeptide, would give an unstable primary carbocation lacking a neighboring nitrogen. The mechanism, thus, only rationalizes the observation of a b(3)-(H(2)O + CO) fragment in RGD and not in the isopeptide. The isomers can be distinguished on the basis of this unique peak or on the basis of the different SORI energy dependence of the formation of the b(3) ions.

Aspartic Acid↗