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At least 865 records · Page 48Linked to original sources
PubMed1988

Mutation of aspartic acid-351, lysine-352, and lysine-515 alters the Ca2+ transport activity of the Ca2+-ATPase expressed in COS-1 cells.

Full-length cDNAs encoding neonatal and adult isoforms of the Ca2+-ATPase of rabbit fast-twitch skeletal muscle sarcoplasmic reticulum were expressed transiently in COS-1 cells. The microsomal fraction isolated from transfected COS-1 cells contained immunoreactive Ca2+-ATPase and catalyzed Ca2+ transport at rates at least 15-fold above controls. No differences were observed in either the rates or Ca2+ dependency of Ca2+ transport catalyzed by the two isoforms. Aspartic acid-351, the site of formation of the catalytic acyl phosphate in the enzyme, was mutated to asparagine, glutamic acid, serine, threonine, histidine, or alanine. In every case, Ca2+ transport activity and Ca2+-dependent phosphorylation were eliminated. Ca2+ transport was also eliminated by mutation of lysine-352 to arginine, glutamine, or glutamic acid or by mutation of Asp351-Lys352 to Lys351-Asp352. Mutation of lysine-515, the site of fluorescein isothiocyanate modification in the enzyme, resulted in diminished Ca2+ transport activity as follows: arginine, 60%; glutamine, 25%; glutamic acid, 5%. These results demonstrate the absolute requirement of acylphosphate formation for the Ca2+ transport function and define a residue important for ATP binding. They also demonstrate the feasibility of a thorough analysis of active sites in the Ca2+-ATPase by expression and site-specific mutagenesis.

Animals↗
PubMed1996

A mutation in which alanine 128 Is replaced by aspartic acid abolishes dimerization of the b-subunit of the F0F1-ATPase from Escherichia coli.

Site-directed mutagenesis was used to investigate the roles of a short series of hydrophobic amino acids in the b-subunit of the Escherichia coli F0F1-ATPase. A mutation affecting one of these, G131D, had been previously characterized and was found to interrupt assembly of the F0F1-ATPase (Jans, D. A., Hatch, L., Fimmel, A. L., Gibson, D., and Cox, G. B. (1985) J. Bacteriol. 162, 420-426). To extend this work, aspartic acid was substituted for each one of the residues from positions 124 to 132. The properties of mutants in this series are consistent with the region from Val124 to Gly131 forming an alpha-helix. Two of the mutations, V124D and A128D, resulted in a similar phenotype to the G131D mutation. This suggested that Val124, Ala128, and Gly131 form a helical face which may have a role in inter- or intrasubunit interactions. This was tested by overexpressing and purifying the cytoplasmic domains of the wild type and A128D mutant b-subunits. Sedimentation equilibrium centrifugation indicated that the wild type domain formed a dimer whereas the mutant was present as a monomer.

Alanine↗
PubMed1999

Four critical aspartic acid residues potentially involved in the catalytic mechanism of Escherichia coli K-12 WaaR.

Escherichia coli K-12 WaaR is a non-processive alpha-1,2 glucosyltransferase, involved in the synthesis of the R-core of lipopolysaccharide. WaaR possesses the four conserved structural regions I, II, III and IV, each presumably involved in the mechanistic function in catalysis. Regions I and III contain the pair of strictly conserved Asp residues. Asp-129, 131 (region I) and 215, 217 (region III) of WaaR were individually converted to Asn by the site-directed mutagenesis of the waaR gene. All mutated enzymes were inactive, supporting the model for an alpha-glycosyl transfer reaction where the pair of strictly conserved aspartic acid residues in regions I and III play a critical role in the catalytic function.

Aspartic Acid↗
PubMed1993

Stability of oxidized Escherichia coli thioredoxin and its dependence on protonation of the aspartic acid residue in the 26 position.

The effects of pH in the range 6.0-8.0 on the thermodynamics of the reversible thermal unfolding of Escherichia coli thioredoxin in the oxidized state have been determined over a range of concentrations using differential scanning calorimetry. The thermal denaturation indicated an inverse temperature dependence on concentration. The data were shown to fit a model based on dimerization of both the native and denatured states of the protein. The degree of dimerization of both states was found to be pH dependent. The previously described importance of protonation of the anomalously titrating aspartic acid 26 residue [Langsetmo, K., Fuchs, J., & Woodward, C. (1991) Biochemistry 30 ,7603-7609] was apparently verified by the agreement between the experimentally determined delta delta Gzerod and the calculated delta delta GzeroH in the pH range 7.0-8.0.

Aspartic Acid↗
PubMed1976

Co-operative ionisation of aspartic-acid-158 and histidine-159 in papain. Evidence from 19F nuclear-magnetic-resonance and fluorescence spectroscopy.

The chemical shift of the single resonance in the 19F nuclear magnetic resonance spectrum of papain which has been irreversibly inhibited by 3-bromo-1,1,1-trifluoropropanone, exhibits pH-dependence. The fluorescence intensity of this papain derivative shows pH-dependence on two groups which exhibit co-operative ionisation. This co-operative behaviour is probably a function of the probe since the fluorescence intensity of S-ethane-thio-papain is dependent on a single ionisation constant, whereas that of S-(2-hydroxyethane)-thio-papain is dependent on two ionisable groups again acting co-operatively. The 1,1,1-trifluoroketone probe will be hydrated in aqueous solution and would be capable of hydrogen bonding with the protein. The two groups detected are considered to be aspartic-acid-158 and histidine-159. The co-operative ionisation of these groups in substrate hydrolysis is discussed.

Aspartic Acid↗
PubMed2005

Synthesis and biological activities of aryl-ether-, biaryl-, and fluorene-aspartic acid and diaminopropionic acid analogs as potent inhibitors of the high-affinity glutamate transporter EAAT-2.

Excitatory amino acid transporters (EAATs) play a pivotal role in maintaining glutamate homeostasis in the mammalian central nervous system, with the EAAT-2 subtype thought to be responsible for the bulk of the glutamate uptake in forebrain regions. A complete elucidation of the functional role of EAAT-2 has been hampered by the lack of potent and selective pharmacological tools. In this study, we describe the synthesis and biological activities of novel aryl-ether, biaryl-, and fluorene-aspartic acid and diaminopropionic acid analogs as potent inhibitors of EAAT-2. Compound (16) represents one of the most potent (IC50=85+/-5 nM) and selective inhibitors of EAAT-2 identified to date.

Aspartic Acid↗
PubMedDate not supplied

A new class of agonists and antagonists of N-methyl-D-aspartic acid receptors: derivatives of imidazole-4,5- and pyrazole-3,4-dicarboxylic acids.

Studies of imidazole-4,5- and pyrazole-3,4-dicarboxylic acid derivatives revealed a number of new agonists and antagonists of N-methyl-D-aspartic acid (NMDA) receptors. Studies were based on whole-cell patch-clamp methods applied to rat hippocampus pyramidal cells. Increases in the lipophilicity of the environment of the nitrogen atom, keeping the distance between the terminal acid functions constant, led to a weakening of NMDA antagonism and increases in NMDA antagonism. Increases in the lipophilicity around the nitrogen atom could also lead to less of selectivity in the interaction with NMDA receptors and the appearance of non-NMDA antagonist properties.

Animals↗
PubMed1993

Multiple effects of spermine on N-methyl-D-aspartic acid receptor responses of rat cultured hippocampal neurones.

1. The modulation by polyamines of responses to N-methyl-D-aspartic acid (NMDA) was studied using a rapid perfusion system and whole-cell voltage-clamp recording from rat hippocampal neurons in dissociated culture. 2. Concentration jump responses to 100 microM NMDA in the presence of 10 microM glycine revealed potentiation by 3 mM spermine at a membrane potential of +60 mV, but depression at -120 mV; the degree of potentiation at +60 mV was variable from cell to cell while marked depression at -120 mV was observed in all cells. The depression of responses to NMDA by spermine was highly voltage dependent (z delta = 1.17) with an apparent equilibrium dissociation constant for block at 0 mV of 27 mM. 3. Analysis of spermine dose-potentiation curves for responses recorded at +60 mV in the presence of 10 microM glycine revealed a half-maximal effect at 125 microM. Under the same conditions, but at -60 mV, analysis of spermine-evoked depression was performed for cells with less than 5% potentiation at +60 mV, and revealed half-maximal inhibition at 344 microM. 4. Dose-response analysis for the glycine-sensitive activation of NMDA receptors at +60 mV revealed a 3.5-fold increase in apparent affinity for glycine in the presence of 1 mM spermine. This increase in affinity for glycine was accompanied by a 3.3-fold decrease in the rate of development of glycine-sensitive desensitization, and a 2.4-fold decrease in the rate of dissociation of glycine from NMDA receptors, while the rate constant for dissociation of NMDA was not reduced. 5. In the presence of non-saturating concentrations of glycine, spermine-induced potentiation at +60 mV developed with two exponential components: a slow glycine-sensitive component, the amplitude and time constant of which decreased with increasing glycine concentration (30 nM glycine, amplitude = 80.2 +/- 5.1%, tau = 780 +/- 79 ms; 3 microM glycine, amplitude = 22.6 +/- 7.1%, tau = 45 +/- 13 ms), and a faster component (tau < 20 ms at all concentrations of glycine), the amplitude of which varied from cell to cell, and which became larger with increase in concentration of glycine. When responses to the application of spermine were measured in the presence 10 microM L-alanine instead of 100 nM glycine, the slow component of potentiation was absent.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1989

Effects of the yeast extract components pyrroloquinoline quinone and aspartic acid on vitamin B12 production in Klebsiella pneumoniae IFO 13541.

The production of vitamin B12 from carbohydrates, peptone, casamino acid, etc., by intestinal bacteria was investigated. Klebsiella pneumoniae IFO 13541 was the most efficient strain for vitamin B12 production, which depended exclusively on the concentration of yeast extract added to the medium. A concentrated solution of yeast extract (1 ml) was chromatographed on a Sephadex G-25 column (1 x 180 cm) and eluted with H2O (eighty fractions of 3 ml each were collected). It was found that fractions in which bacterial growth was most prevalent also exhibited the highest amount of vitamin production. The effectiveness of yeast extract was shown by the participation of pyrroloquinoline quinone and aspartic acid in the growth stimulation and in the vitamin B12 production in this strain.

Acetobacter↗
PubMed2000

N-Methyl-D-aspartic acid- and metaphit-induced audiogenic seizures in rat model of seizures.

The effects of NMDA (N-methyl-D-aspartic acid) on metaphit (1-[1(3-isothiocyanatophenyl)-cyclohexyl]piperidine)-induced audiogenic seizures in adult male Wistar albino rats were studied with the aim of developing a suitable animal model of seizures. The animals were divided into four experimental groups: 1, saline control; 2, metaphit-injected; 3, metaphit + NMDA administered and 4, NMDA-treated. Upon the treatment, the rats were exposed to sound stimulation (100 +/- 3 dB, for 60 s) at hourly intervals and the incidence and severity (running, clonus and tonus) of seizures were analysed. In group 3, only the animals which did not exhibit any metaphit-induced audiogenic seizures over 8 h were given a subconvulsive NMDA dose after the eighth audiogenic testing. For EEG recordings, three gold-plated screws were implanted into the rat skull. In most animals, metaphit led to EEG abnormalities and elicited epileptiform activity recorded as spikes, polyspikes and spike-wave complexes. Maximum incidence and severity of metaphit-induced convulsions occurred 8 h after injection (incidence 9/12), abating gradually until disappearing 30 h later. NMDA alone provoked no seizure response but the initial signs characterized by isolated spike activity evolving into sporadic slow-wave complexes, thus representing a proconvulsive brain state, were observed. This compound led to stereotyped behaviour seen as asymmetric posture, loss of righting reflex and tonic hind limb extension lasting for 60-90 min. It also potentiated metaphit-induced audiogenic seizures. Potentiation of metaphit-related audiogenic seizures by NMDA was recorded in three out of 17 rats that had never displayed seizures in eight previous testings, with a maximum incidence of eight out of 17 animals, 13-14 h after metaphit administration and seizures lasted for 10 h.

Animals↗
PubMed1993

Effect of a single intravenous injection of N-methyl-D,L-aspartic acid on secretion of luteinizing hormone and growth hormone in Holstein bull calves.

The role of N-methyl-D-aspartate (NMDA) receptor activation in the central regulation of luteinizing hormone (LH) and growth hormone (GH) was tested by administering a bolus intravenous dose of N-methyl-D,L-aspartic acid (NMA), a NMDA receptor agonist, to 24-week-old intact (n=5), estradiol-treated intact (n=3) and castrated (n=3) Holstein bull calves. The calves were bled for 12h pre- and 100 min post-NMA injection (1.75 mg-/kgBW) periods at 10 min intervals. Concentrations of LH and GH in plasma were measured by specific RIA. Prior to administration of NMA, the average concentration of LH, but not GH, differed significantly among the 3 groups. As expected, administration of estradiol prevented the normal ontogeny of pulsatile LH secretion, while castration resulted in an increased frequency of LH discharges. Injection of NMA resulted in an acute (P<0.001) release of LH in 3 of 5 intact and 3 of 3 estradiol-treated intact calves with the peak response being observed at 20 min (3.18 +/- 1.3 and 5.58 +/- 1.3 ng/ml, respectively) following the challenge. Treatment with NMA did not alter the release of LH in castrate calves. Concentrations of GH in plasma increased (P<0.001) within 20 to 30 min after administration of NMA in intact, estradiol-treated intact and castrate calves with a similar response being observed in each group. Based on these findings, we suggest an involvement of glutamatergic neurotransmission in the hypothalamic or supra-hypothalamic control of LH and GH secretion, and that the excitatory effects of NMDA receptor activation on LH release are overtly influenced by gonadal steroids in bull calves.

Animals↗
PubMed1998

Effects of N-methyl-D-aspartic acid and kainic acid on prolactin secretion in hyper- and hypoprolactinaemic conditions.

OBJECTIVE: The stimulatory and inhibitory effects of N-methyl-D-aspartic acid (NMDA) and kainic acid on prolactin (PRL) secretion have been correlated with the serum prolactin concentrations before drug administration. In the present experiments, we analysed the role of NMDA and kainic acid in PRL secretion in females with different serum concentrations of PRL. METHODS: Hypoprolactinaemic females were obtained by ovariectomy or after administration of diethyldithiocarbamate (an inhibitor of dopamine-beta-hydroxylase). Chronic hyperprolactinaemia was induced by neonatal administration of testosterone or oestradiol and acute hyperprolactinaemia was induced either by administration of alpha-methyl-p-tyrosine (an inhibitor of tyrosine hydroxylase) or by ether exposure. To analyse the role of dopamine in the effects of NMDA, we measured pituitary concentrations of dopamine after NMDA treatment and the effects of pretreatment with domperidone. RESULTS: (1) NMDA, but not kainic acid, stimulated PRL release in cyclic females. This effect was independent of serum PRL concentrations and was not accompanied by a decrease in pituitary concentrations of dopamine. (2) NMDA did not change PRL secretion in neonatally androgenized females, whereas NMDA and kainic acid inhibited PRL release in neonatally oestrogenized females. The inhibitory effects of NMDA and kainic acid were blocked by domperidone. (3) Kainic acid inhibited PRL secretion in prepubertal hyper- and hypoprolactinaemic rats. (4) Hyperprolactinaemia induced by ether stress was counteracted by administration of NMDA and kainic acid. CONCLUSIONS: (a) NMDA has a dual effect on prolactin secretion that is independent of prior prolactin concentrations and of dopamine activity, but kainic acid is only inhibitory. (b) The stimulatory or inhibitory effects of NMDA and kainic acid on PRL secretion were not strictly related to basal PRL concentrations and necessarily involved a change in the secretion of prolactin releasing factors, as no correlations were observed between changes in pituitary concentrations of dopamine and serum PRL concentrations. (c) Females rendered hyperprolactinaemic by neonatal administration of testosterone or oestradiol responded differently after NMDA administration. (d) NMDA and kainic acid blocked the mechanisms involved in stress-induced PRL secretion.

Animals↗
PubMed2006

Non-vagal apnea evoked by intra-common carotid artery injection of N-methyl-D-aspartic acid (NMDA) in anesthetized rats.

Respiratory effects of an intra-common carotid artery injection of N-methyl-D-aspartic acid (NMDA) were investigated in anesthetized spontaneously breathing rats, using three experimental paradigms: (1) midcervical vagotomy followed by supranodosal vagotomy, (2) midcervical vagotomy followed by section of the carotid sinus nerves (CSNs), and (3) midcervical vagotomy followed by pharmacological blockade of NMDA receptors. The intra-common carotid artery injection of NMDA (4 mg/kg) induced transient expiratory apnea followed by a brief and variably occurring period of breathing at reduced tidal volume. There were no consistent changes in respiratory rate in rats subjected to midcervical vagotomy alone. Supranodose vagotomy exerted no effect on NMDA-induced respiratory arrest, whereas CSNs' section or blockade of NMDA receptors with AP-7 abolished the apnea. These results indicate that the apnea induced by intra-arterial NMDA challenge is due to activation of peripheral NMDA receptors and is mediated via carotid body afferents.

2-Amino-5-phosphonovalerate↗
PubMed1998

Aggrecan turnover in human articular cartilage: use of aspartic acid racemization as a marker of molecular age.

Aggrecan is a key component of the cartilage matrix. During aging, many changes occur in its composition and structure; in particular, there is an increase in the proportion of lower molecular weight monomers and of the "free" binding region. An important question has been whether these changes represent alterations in biosynthesis or whether they are due to the accumulation with age of the partially degraded fragments of the originally synthesized large monomer. In the present work we have used an independent tool, viz., the extent of racemization of aspartic acid to study the molecular "age" of different buoyant density fractions of the aggrecan of human articular cartilage, as well as of isolated free binding region and link protein. By measuring the D/LAsp ratio of the different aggrecan species, we were able to establish directly the relative residence times of these molecules in the cartilage matrix and, in combination with compositional and structural analyses, to define their "history" and calculate some of the kinetics constants characterizing their turnover. The value of the turnover constant for the large monomer in fraction A1D1 is 0.206 per year, which corresponds to a half-life of 3.4 years, while the turnover constant for the free binding region is 0.027 per year, which corresponds to a half-life of 25 years. It is thus clear that the rate of formation and turnover of the large monomer is much more rapid than the final degradation of the free binding region fragments, which explains the accumulation of the latter in cartilage during aging.

Adult↗
PubMed2002

Analysis of the aspartic acid metabolic pathway using mutant genes.

Amino acid metabolism is a fundamental process for plant growth and development. Although a considerable amount of information is available, little is known about the genetic control of enzymatic steps or regulation of several pathways. Much of the information about biochemical pathways has arisen from the use of mutants lacking key enzymes. Although mutants were largely used already in the 60's, by bacterial and fungal geneticists, it took plant research a long time to catch up. The advance in this area was rapid in the 80's, which was followed in the 90's by the development of techniques of plant transformation. In this review we present an overview of the aspartic acid metabolic pathway, the key regulatory enzymes and the mutants and transgenic plants produced for lysine and threonine metabolism. We also discuss and propose a new study of high-lysine mutants.

Aspartate Kinase↗