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PubMed2003

Free D-aspartic acid in rat salivary glands.

Free D-aspartic acid (D-Asp) has been reported to occur in a wide variety of tissues and cells, exclusively in central nervous system and endocrine tissues. In this manuscript, we demonstrate that large amounts of D-Asp are present in the exocrine tissue, salivary glands. In adult male rats, D-Asp concentrations in parotid and submandibular gland were 212+/-68 and 233+/-34 nmol/g wet weight, respectively, and were low (38+/-20 nmol/g wet weight) in sublingual gland. This result indicates that substantial level of D-Asp exists not only in central nervous system and endocrine tissues but also in exocrine tissues. Furthermore, D-Asp concentration in parotid gland increased transiently at 3 weeks of age and decreased thereafter. In contrast, the D-Asp level in submandibular gland continued to increase gradually from 1 to 7 weeks of age and remained at an adult level after 7 weeks of age. Using anti-D-Asp antibody, immunohistochemical study was done against these glands and it showed that the predominant localization of D-Asp in acinar cells in parotid gland, while D-Asp is specifically located in striated duct cells in submandibular gland. These results suggest that D-Asp may play different roles between the two glands.

Aging↗
PubMedDate not supplied

The effect of aspartic acid on the intensity of physical dependence in morphine dependent mice.

The mice (Balb/C strain) given 2% aspartic acid in 5% saccharose solution or only saccharose solution (p. os) starting 12 hr before the sc morphine pellet implantation until the removal of pellet were rendered physically morphine dependent. During the development of morphine dependence and after the removal of pellets (on 3-d day) spontaneous motor activity and analgesic threshold were measured as reliable abrupt withdrawal signs. Aspartic acid prevented to some extent the appearance of symptoms of physical morphine dependence.

Analgesia↗
PubMed2004

An invariant aspartic acid in the DNA glycosylase domain of DEMETER is necessary for transcriptional activation of the imprinted MEDEA gene.

Helix-hairpin-helix DNA glycosylases are typically small proteins that initiate repair of DNA by excising damaged or mispaired bases. An invariant aspartic acid in the active site is involved in catalyzing the excision reaction. Replacement of this critical residue with an asparagine severely reduces catalytic activity but preserves enzyme stability and structure. The Arabidopsis DEMETER (DME) gene encodes a large 1,729-aa polypeptide with a 200-aa DNA glycosylase domain. DME is expressed primarily in the central cell of the female gametophyte. DME activates maternal allele expression of the imprinted MEDEA (MEA) gene in the central cell and is required for seed viability. We mutated the invariant aspartic acid at position 1304 in DME to asparagine (D1304N) to determine whether the catalytic activity of the DNA glycosylase domain is required for DME function in vivo. Transgenes expressing wild-type DME in the central cell rescue seed abortion caused by a mutation in the endogenous DME gene and activate maternal MEA:GFP transcription. However, transgenes expressing the D1304N mutant DME do not rescue seed abortion or activate maternal MEA:GFP transcription. Whereas ectopic expression of the wild-type DME polypeptide in pollen is sufficient to activate ectopic paternal MEA and MEA:GUS expression, equivalent expression of the D1304N mutant DME in pollen failed to do so. These results show that the conserved aspartic acid residue is necessary for DME to function in vivo and suggest that an active DNA glycosylase domain, normally associated with DNA repair, promotes gene transcription that is essential for gene imprinting.

Arabidopsis Proteins↗
PubMed1976

Antitumor activity of N-(phosphonacetyl)-L-aspartic acid, a transition-state inhibitor of aspartate transcarbamylase.

N-(Phosphonacetyl)-L-aspartate (PALA) is an analog of the transition state for the aspartate transcarbamylase reaction and has been reported previously to be a potent and specific inhibitor of de novo pyrimidine nucleotide biosynthesis. It is now shown that PALA has considerable antitumor activity against certain transplantable tumors in mice. PALA, unlike other antimetabolites, was less effective against ascitic leukemias than against two solid tumors, B16 melanoma and Lewis lung carcinoma. Another solid tumor, Ridgway osteogenic sarcoma, which is sensitivie to many established chemotherapeutic agents, did not respond to PALA. Daily or intermittent treatment with PALA did not significantly increase the life-span of mice bearing i.p. leukemia L1210. The survival time of mice bearing i.p. P388 leukemia was prolonged by PALA treatment by up to 64%. In a number of experiments mice bearing i.p. B16 melanoma survived 77 to 86% longer than did controls when treated with PALA (490 mg/kg) on Days 1, 5, and 9. Lewis lung carcinoma, a tumor refractory to most established antineoplastic agents, was highly sensitive to PALA. Treatment on Days 1, 5, and 9 following s.c. implantation of Lewis lung carcinoma was curative to 50% of the mice. If treatment was delayed until s.c. Lewis lung tumors had reached about 500 mg, PALA neither cured the mice nor produced significant tumor regression. However, extensive delay of tumor growth and prolongation of survival were still observed.

Animals↗
PubMed1986

Thermodynamics of the conversion of aqueous L-aspartic acid to fumaric acid and ammonia.

The thermodynamics of the conversion of aqueous L-aspartic acid to fumaric acid and ammonia have been investigated using both heat conduction microcalorimetry and high-pressure liquid chromatography. The reaction was carried out in aqueous phosphate buffer over the pH range 7.25-7.43, the temperature range 13-43 degrees C, and at ionic strengths varying from 0.066 to 0.366 mol kg(-1). The following values have been found for the conversion of aqueous L-aspartateH- to fumarate2- and NH4+ at 25 degrees C and at zero ionic strength: K = (1.48 +/- 0.10) x 10(-3), DeltaG degrees = 16.15 +/- 0.16 kJ mol(-1), DeltaH degrees = 24.5 +/- 1.0 kJ mol(-1), and DeltaC(p) degrees = -147 +/- 100 J mol(-1) K(-1). Calculations have also been performed which give values of the apparent equilibrium constant for the conversion of L-aspartic acid to fumaric acid and ammonia as a function of temperature, pH and ionic strength.

Journal Article↗
PubMed1992

Aspartic acid as a trap for gamma-radiation energy in the amorphous Al5(OH)15(Asp)3.3H2O.

Paramagnetic molecular centers produced by gamma irradiation at 77 K and at room temperature in the novel compound Al5(OH)15(Asp)3.3H2O were studied by ESR spectroscopy. The g value of 2.0034 and the lack of such lines in pure aluminum hydroxide suggested that all the paramagnetic centers observed are related to the aspartic acid molecule. However, none of the paramagnetic centers gave an ESR spectrum characteristic for gamma-irradiated pure aspartic acid powder. The influence of the oxygen on the formation of the paramagnetic centers was noticed. The extreme stability of the paramagnetic molecular centers formed in Al5(OH)15(Asp)3.3H2O suggests that aspartic acid complexed in aluminum hydroxide is a good trap for gamma-radiation energy.

Aluminum Hydroxide↗
PubMed2004

[Aspartic Acid and mannitol enhance protective efficiency of asanquineous cardioplegic solution].

The aim of this work was to assess effects of a novel asanquineous cardioplegic solution (CP-5), buffered with trisamine (pH 7.6+/-0.1 at 22 degrees C) and containing 21.5 mM aspartic acid and 20.0 mM mannitol, on postischemic functional and metabolic recovery of isolated rat heart. A modified Ringer solution with 25 mM KCl (pH 7.6+/-0.1 at 22 degrees C) and the St. Thomas' cardioplegic solution (pH 7.8+/-0.1 at 22 degrees C) were used as controls. Osmolarity of all cardioplegic solutions were 340+/-5. After 20-min initial perfusion according to Neely (steady state) the hearts were subjected to 40-min normothermal total ischemia followed by 30-min antegrade reperfusion. Cardioplegic solutions were infused prior to ischemia at rate of the initial coronary flow for 5 min at room temperature. During reperfusion the hearts of CP-5 group completely recovered coronary flow and significantly enhanced restoration of the majority functional indices compared to the hearts in both control groups. This effect was combined with less lactate accumulation and preservation of higher ATP and phosphocreatine (PCr) levels in the heart tissue by the end of ischemia and, probably was induced by inclusion of aspartic acid into composition of CP-5. By the end of reperfusion the hearts treated with CP-5 completely recovered PCr content and restored ATP level up to 65.2+/-4.6% of initial one. A better energy state of reperfused hearts in CP-5 group was accompanied by reduction of myocardial lactate tissue to the preischemic value. Restoration of ATP, PCr and lactate content was significantly poor in both control groups during reperfusion. The least formation of a spin adduct of the short life oxygen radicals was found in the myocardial effluent of the hearts of CP-5 group at the early reperfusion using EPR technique. These data suggest a reduced release of oxygen radical generating systems from postischemic myocardium into perfusate due to antioxidant effect of mannitol. The obtained results substantiate addition of aspartic acid and mannitol to the asanquineous cardioplegic solution, buffered with trisamine, to enhance efficacy of myocardial protection against ischemia and reperfusion injury.

Animals↗
PubMed2006

Age-dependent changes in the racemisation ratio of aspartic acid in human alveolar bone.

We investigated the racemisation ratio of aspartic acid (Asp) in alveolar bone. In addition, we designed and created a new column to detect Asp in a short period of time, which allowed us to detect d-Asp and l-Asp separately from each other within 5min. Comparing identical ages, the racemisation ratio of alveolar bone was generally lower than that of other bones reported so far. This result suggests that alveolar bone is metabolically more active than other bones, as expected. The rate constant for the racemisation reaction (k(y)) of alveolar bone was calculated to be 0.000338 in males and 0.000084 in females. The rate constants in males and females were each similar to the respective ratios of the femur. This result suggests that the age-dependent reduction in metabolic turnover in alveolar bone proceeds similarly to that in the femur, although those changes proceed more slowly in females than in males. The correlation coefficient between the racemisation ratio of alveolar bone and chronological age was 0.660. It was high in males (r=0.912) and low in females (r=0.527), and this gender difference was statistically significant (P: 0.01-0.001), as in the femur.

Adolescent↗
PubMed1992

Repetitive injections of L-glutamic acid, in contrast to those of N-methyl-D,L-aspartic acid, fail to elicit sustained hypothalamic GnRH release in the prepubertal male rhesus monkey (Macaca mulatta).

The purpose of the present study was to examine whether repetitive intravenous injections of L-glutamic acid (Glu), like those of N-methyl-D,L-aspartic acid (NMA), are able to elicit a sustained train of gonadotropin releasing hormone (GnRH) discharges from the hypothalamus of the prepubertal male monkey. In order to utilize pituitary luteinizing hormone (LH) secretion as a bioassay of hypothalamic GnRH release, the responsiveness of the gonadotroph of the prepubertal animals was enhanced prior to the study with a chronic intermittent intravenous infusion of the synthetic decapeptide (0.1 microgram/min for 3 min every h). Sequential intravenous injections of Glu (150 mg/kg BW) were administered at 3-hour intervals for 6 or 24 h. Although the first injection of this acidic amino acid elicited a robust discharge of GnRH, subsequent stimulation with Glu resulted in GnRH discharges with progressively decreasing magnitudes, and by the 9th injection Glu-induced GnRH release was abolished. Peak concentrations of circulating Glu following the 1st and 4th Glu injection were indistinguishable (3,959 +/- 437 vs. 4,139 +/- 72 nmol/ml, respectively). Interestingly, the failure of repetitive intravenous injections of Glu to sustain pulsatile GnRH release was not associated with a loss of responsiveness to NMA administration, nor was it accompanied by a corresponding decrement in Glu induced growth hormone (GH) discharges. As previously demonstrated, repetitive intravenous administration of NMA (2-5 mg/kg BW) every 3 h for 9 h sustained pulsatile GnRH secretion without decrement. A similar intermittent infusion of kainic acid (KA; 1 mg/kg BW every 3 h for 6 h), however, elicited a GnRH response that mimicked that observed in response to intermittent Glu treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

L-aspartic acid potentiates 'slow' inward current in cultured spinal cord neurons.

Intracellular recordings (current- and two electrode voltage-clamp) were made from mouse spinal cord neurons grown dissociated in tissue culture. Neurons were bathed in elevated concentrations of calcium (Ca) and sometimes tetraethylammonium (TEA). Brief depolarizing current injections activated graded 'after-depolarizations' which summated to trigger prolonged all-or-none action potentials. Under voltage-clamp both of these active potentials were manifest as 'slow' inward current. Net inward current was observed in some neurons during 0.5-1.0 s depolarizing command steps. However, in the majority of cases the inward current was seen as large inward current tails (outward current relaxations) upon repolarization of the membrane potential to holding values. Cadmium (Cd) blocked this slow inward current, 'after-depolarizations' and prolonged action potentials. Applications of L-aspartic acid increased the magnitude of net inward current evoked by command steps and potentiated and prolonged inward current tails. This potentiation and prolongation of voltage-dependent inward current likely accounts for the prolonged action potentials or 'bursting' characteristic of responses to L-aspartic acid and related amino acids such as N-methyl-D-aspartic acid.

Animals↗
PubMed2006

Lack of association of a variable number of aspartic acid residues in the asporin gene with osteoarthritis susceptibility: case-control studies in Spanish Caucasians.

A recent genetic association study has identified a microsatellite in the coding sequence of the asporin gene as a susceptibility factor for osteoarthritis (OA). Alleles of this microsatellite determine the variable number of aspartic acid residues in the amino-terminal end of the asporin protein. Asporin binds directly to the growth factor transforming growth factor beta and inhibits its anabolic effects in cartilage, which include stimulation of collagen and aggrecan synthesis. The OA-associated allele, with 14 aspartic acid residues, inhibits the anabolic effects of transforming growth factor beta more strongly than other asporin alleles, leading to increased OA liability. We have explored whether the association found in several cohorts of Japanese hip OA and knee OA patients was also present in Spanish Caucasians. We studied patients that had undergone total joint replacement for primary OA in the hip (n = 303) or the knee (n = 188) and patients with hand OA (n = 233), and we compared their results with controls (n = 294) lacking overt OA clinical symptoms. No significant differences were observed in any of the multiple comparisons performed, which included global tests of allele frequency distributions and specific comparisons as well as stratification by affected joint and by sex. Our results, together with reports from the United Kingdom and Greece, indicate that the stretch of aspartic acid residues in asporin is not an important factor in OA susceptibility among European Caucasians. It remains possible that lifestyle, environmental or genetic differences allow for an important effect of asporin variants in other ethnic groups as has been reported in the Japanese, but this should be supported by additional studies.

Arthroplasty, Replacement, Hip↗
PubMed1983

Effect of glutamic and aspartic acids on adenine nucleotides, nitrogenous compounds and contractile function during underperfusion of isolated rat heart.

The experiments were carried out to find out whether exogenous glutamic or aspartic acid could diminish changes in the cardiac contractile function and high-energy phosphate content caused by underperfusion of isolated isovolumic rat heart. After 40 min of reduced coronary flow (from 10 to 3 ml/min) there was an almost four-fold fall in the developed pressure, and more than three-fold rise in the diastolic pressure as well as a profound fall in creatine phosphate (CP) and ATP content. Glutamic (68 mM) or aspartic (75 mM) acids were added to the perfusate after 10 min of underperfusion when the developed pressure had declined almost to the same level as was observed after 40 min and the content of CP was reduced more than two-fold. Glutamic acid completely prevented the rise in the diastolic pressure and significantly increased the CP content, as compared to its level observed before addition of glutamate, but glutamic acid did not change the developed pressure. As a result, the CP and ATP contents were three- and two-fold higher, respectively, after addition of glutamic acid as compared to control underperfused hearts. Similar, but slightly less prominent effects were observed when aspartic acid was added instead of glutamic acid. These results suggest that high concentrations of glutamic and aspartic acids can exert beneficial effects on ischemic heart muscle.

Adenine Nucleotides↗
PubMed2001

[Determination of the D-and L-forms of aspartic acid in intervertebral disk tissue as an indicator of age].

Assessment of age according to racemization coefficient of aspartic acid in dentin is considered a reliable method. Proteins which are isolated from dentin are non-collagenous proteins or collagen. As collagen is one of the most frequent proteins in the human body, the question arises whether the D-form of aspartic acid can be assessed also in other tissues and the racemization coefficient used for assessment of age. In the submitted work the author assessed to use the racemization coefficient in the tissue of the intervertebral disk. A lyophilized portion of the annulus fibrosus was hydrolyzed and the amino acids of the hydrolysate were estimated after derivation by gas chromatography on a chiral capillary column. The values of the racemization coefficient indicate limited possibilities to assess age from thus prepared tissue.

Adolescent↗
PubMed1989

Site-directed mutagenesis of m1 muscarinic acetylcholine receptors: conserved aspartic acids play important roles in receptor function.

Muscarinic acetylcholine receptors contain a region encompassing the second and third transmembrane domains that is rich in conserved aspartic acid residues. To investigate the role of four conserved aspartic acids at positions 71, 99, 105, and 122 in muscarinic receptor function, point mutations in the rat m1 muscarinic receptor gene were made that converted each Asp to Asn, and wild type or mutant genes were stably expressed in Chinese hamster ovary cells that normally lack muscarinic receptors. Substitution of Asp71 or Asp122 with Asn produced mutant receptors that displayed high affinity for carbachol but decreased efficacy and potency, respectively, in agonist-induced activation of phosphoinositide hydrolysis, suggesting that these residues may mediate receptor-GTP binding protein interactions. Substitution of Asp99 or Asp105 with Asn produced marked decreases in ligand binding affinities and/or covalent incorporation of [3H] propylbenzilylcholine mustard, suggesting that these residues may be involved in receptor-ligand interactions.

Animals↗
PubMed1989

The alpha subunit of tryptophan synthase. Evidence that aspartic acid 60 is a catalytic residue and that the double alteration of residues 175 and 211 in a second-site revertant restores the proper geometry of the substrate binding site.

Our studies, which are aimed at understanding the catalytic mechanism of the alpha subunit of tryptophan synthase from Salmonella typhimurium, use site-directed mutagenesis to explore the functional roles of aspartic acid 60, tyrosine 175, and glycine 211. These residues are located close to the substrate binding site of the alpha subunit in the three-dimensional structure of the tryptophan synthase alpha 2 beta 2 complex. Our finding that replacement of aspartic acid 60 by asparagine, alanine, or tyrosine results in complete loss of activity in the reaction catalyzed by the alpha subunit supports a catalytic role for aspartic acid 60. Since the mutant form with glutamic acid at position 60 has partial activity, glutamic acid 60 may serve as an alternative catalytic base. The mutant form in which tyrosine 175 is replaced by phenylalanine has substantial activity; thus the phenolic hydroxyl of tyrosine 175 is not essential for catalysis or substrate binding. Yanofsky and colleagues have identified many missense mutant forms of the alpha subunit of tryptophan synthase from Escherichia coli. Two of these inactive mutant forms had either tyrosine 175 replaced by cysteine or glycine 211 replaced by glutamic acid. Surprisingly, a second-site revertant which contained both of these amino acid changes was partially active. These results indicated that the second mutation must compensate in some way for the first. We now extend the studies of the effects of specific amino acid replacements at positions 175 and 211 by two techniques: 1) characterization of several mutant forms of the alpha subunit from S. typhimurium prepared by site-directed mutagenesis and 2) computer graphics modeling of the substrate binding site of the alpha subunit using the x-ray coordinates of the wild type alpha 2 beta 2 complex from S. typhimurium. We conclude that the restoration of alpha subunit activity in the doubly altered second-site revertant results from restoration of the proper geometry of the substrate binding site.

Aspartic Acid↗
PubMed1993

Aspartic acid 320 is required for optimal activity of rat pancreatic cholesterol esterase.

The acidic amino acid residue required for the catalytic activity of rat pancreatic cholesterol esterase has been identified in this study by sequence comparison with other serine esterases and by site-directed mutagenesis experiments. The sequence comparison studies identified 3 acidic residues in homologous domains between cholesterol esterase, acetylcholinesterase, cholinesterase, and Geotrichum candida lipase that may potentially be the catalytic acidic residue in these proteins. The role of Glu78, Asp79, and Asp320 in the catalytic activity of rat cholesterol esterase was then addressed by mutagenesis and expression of the cDNA. Results showed that replacement of Glu78 or Asp79 with alanine has no effect on the ability of the cholesterol esterase to hydrolyze the artificial water-soluble substrate p-nitrophenyl butyrate. In contrast, the Asp320-->Ala320 substitution abolished the enzyme activity of the cholesterol esterase. The specific requirement of Asp320 for optimal enzyme activity was demonstrated by substitution of the aspartic acid with glutamic acid, thus retaining the charge unit at this position. The Asp320-->Glu320 substitution resulted in an enzyme that displayed normal interaction with bile salt. However, catalytic activity of this mutagenized protein was reduced by approximately 50%. These results strongly suggested that aspartic acid 320 is an important component of the catalytic triad of pancreatic cholesterol esterase. The specific requirement of aspartic acid, instead of glutamic acid, for optimal activity is different from that of other members of the serine esterase gene family.

Acetylcholinesterase↗
PubMed1993

Participation of aspartic acid and pyrroloquinoline quinone in vitamin B12 production in Klebsiella pneumoniae IFO 13541.

Vitamin B12 production by Gram-negative facultative anaerobic intestinal bacteria, members of the family Enterobacteriaceae, was examined. Klebsiella pneumoniae IFO 13541 was the most effective strain with regard to such production. The growth of the strain and its production of vitamin B12 depended exclusively on the concentration of yeast extract added to the medium. The yeast extract components required for the stimulation of bacterial growth and or vitamin B12 production were identified as aspartic acid and pyrroloquinoline quinone (PQQ) and the relationship between vitamin B12 production and these two components was examined. The metabolism of aspartic acid in this process was also investigated; the major metabolites were alanine, glutaminic acid, and valine. The formation of alanine depended on dehydrogenase, the activity of which was greatly increased with increasing PQQ concentration.

Alanine↗
PubMed1999

Mutation of a highly conserved aspartic acid in the beta2 adrenergic receptor: constitutive activation, structural instability, and conformational rearrangement of transmembrane segment 6.

Movements of transmembrane segments (TMs) 3 and 6 play a key role in activation of G protein-coupled receptors. However, the underlying molecular processes that govern these movements, and accordingly control receptor activation, remain unclear. To elucidate the importance of the conserved aspartic acid (Asp-130) in the Asp-Arg-Tyr motif of the beta2 adrenergic receptor (beta2AR), we mutated this residue to asparagine (D130N) to mimic its protonated state, and to alanine (D130A) to fully remove the functionality of the side chain. Both mutants displayed evidence of constitutive receptor activation. In COS-7 cells expressing either D130N or D130A, basal levels of cAMP accumulation were clearly elevated compared with cells expressing the wild-type beta2AR. Incubation of COS-7 cell membranes or purified receptor at 37 degrees C revealed also a marked structural instability of both mutant receptors, suggesting that stabilizing intramolecular constraints had been disrupted. Moreover, we obtained evidence for a conformational rearrangement by mutation of Asp-130. In D130N, a cysteine in TM 6, Cys-285, which is not accessible in the wild-type beta2AR, became accessible to methanethiosulfonate ethylammonium, a charged, sulfhydryl-reactive reagent. This is consistent with a counterclockwise rotation or tilting of TM 6 and provides for the first time structural evidence linking charge-neutralizing mutations of the aspartic acid in the DRY motif to the overall conformational state of the receptor. We propose that protonation of the aspartic acid leads to release of constraining intramolecular interactions, resulting in movements of TM 6 and, thus, conversion of the receptor to the active state.

Animals↗