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At least 703 records · Page 39Linked to original sources
PubMed1998

Emergence of D-aspartic acid in the differentiating neurons of the rat central nervous system.

The rat embryonic brain was probed with anti-d-aspartic acid (d-Asp) antiserum at different stages of development. At gestational day (E) 12, weak immunoreactivity (IR) of d-Asp was apparent at the hindbrain, midbrain and caudal forebrain, whereas it became more intense and extended over the whole brain at E20. However, IR markedly decreased after parturition. In the region of the immature forebrain at an early stage of development (E12), IR was mainly a characteristic of the cytoplasm of the neuronal cells, while in the more mature hindbrain it was localized in the axonal zone. In the more differentiated forebrain at a later stage of development (E18), the IR became restricted to zones which mainly consisted of axons and processes. Consequently, in the rat central nervous system, d-Asp first emerges during embryonic development as a feature of the cytoplasm and thereafter spreads into the axonal regions of neuronal cells, before disappearing almost completely after parturition.

Animals↗
PubMed2005

Studies on the mechanism of aspartic acid cleavage and glutamine deamidation in the acidic degradation of glucagon.

In this study, the polypeptide hormone glucagon was used as a model to investigate the mechanisms of aspartic acid cleavage and glutaminyl deamidation in acidic aqueous solutions. Kinetic studies have shown that cleavage at Asp-21 occurred at significantly slower rates than at Asp-9 and Asp-15 while deamidation rates were similar at the three Gln residues. The role of side-chain ionization in the cleavage mechanism was investigated by determining the pK(a) values of the three Asp residues using TOCSY and NOESY NMR methods. The role of proton transfer was investigated using kinetic solvent isotope effect studies (KSIE). The pK(a) values for the sidechains of Asp-9, Asp-15, and Asp-21 were found to be 3.69, 3.72, and 4.05 respectively. No kinetic solvent isotope effect was observed for the cleavage reaction whereas an inverse effect was observed for deamidation. Based on the lack of sequence effects, pH-rate behavior, and KSIE, the deamidation mechanism was proposed to involve direct hydrolysis of the amide side-chain by water. Based on substrate ionization, pH-rate profiles, and KSIE, the proposed mechanism for Asp cleavage involved nucleophilic attack of the ionized side-chain carboxylate on the protonated carbonyl carbon of the peptide bond to give a cyclic anhydride intermediate.

Animals↗
PubMed1980

Embryotoxicity in mice of phosphonacetyl-L-aspartic acid (PALA), a new antitumor agent. I. Embryolethal, teratogenic, and cytogenetic effects.

The embryolethal and teratogenic effects of phosphonacetyl-L-aspartic acid (PALA), a new antitumor agent, were evaluated in pregnant Swiss albino mice that received multiple IP injections of drug on days 7-11 of gestation. The effects of single doses of PALA given IP on days 4, 5, 6, 7, 8, 9, or 10 of gestation were also examined. Cytogenetic studies were performed on cells from embryos exposed in utero to embryotoxic doses of PALA, as well as on human peripheral leucocytes incubated with PALA for six or 48 hours. When given on days 7-11 of gestation, marked embryolethal effects were noted at PALA doses of 1.5 mg/kg/day, and no embryos survived doses of 6.25 mg/kg/day. Studies on the effects of PALA administered as a single dose on various days of gestation revealed that its embryolethal effects were gestation stage-specific; 80% of embryos were killed in utero after exposure to a dose of 12.5 mg/kg on day 8, whereas doses nearly 20-fold higher (200 mg/kg) were required to exert equivalent embryolethal effects on day 6 or 10 of gestation. PALA treatment induced an increase primarily in the incidence of malformations which occur spontaneously in control mice rather than in malformations not normally seen in controls. PALA embryotoxicity in mice apparently does not derive from major cytogenetic damage, as the incidence of chromosomal aberrations was not significantly increased by in vitro or in vivo exposure to PALA.

Abnormalities, Drug-Induced↗
PubMed2001

[Evalution of activity of acid aspartic proteinase in Candida strains isolated from oral cavity of patients with increased risk of mycosis].

We have evaluated the activity of acid aspartic protease in 195 strains of Candida isolated from the oral cavity of three groups of patients. The first group comprised patients with cancer of the larynx qualified for surgery, the second- patients with neoplastic disease ( Hodgkin s disease, lymphoma, acute granulocytic leukaemia, lymphatic leukaemia, lung cancer, multiple myeloma, stomach cancer, breast cancer) who were not treated, the third group- patients with neoplastic diseases treated by chemotherapy. The strains of fungi were differentiated using API 20C and Api 20C AUX tests according to the protocol adopted at the Department of Medical Parasitology and Biology, Medical University of Lódz. The activity of acid protease was studied by Staib method in Rózga modification. Almost all strains showed high and very high proteolytic activity. The rang of proteolysis zone of Candida strains from the three groups of patients varied from 2,5 to 12,5 mm. We have found the mean proteolytic zones of strains isolated from groups I and III differed statistically significantly (p<0,001). Similarly, statisticall sihnificant difference was seen between these parameters for groups II and III (p<0,05), while there was no difference between strains from group I and II.

Aspartic Acid Endopeptidases↗
PubMed2004

Localization of Rac2 via the C terminus and aspartic acid 150 specifies superoxide generation, actin polarity and chemotaxis in neutrophils.

Despite having a high degree of sequence similarity, the Rho guanosine triphosphatases Rac1 and Rac2 regulate distinct functions in neutrophils. Here we demonstrate that the unique Rac2 localization and functions in neutrophils are regulated by two separate C-terminal motifs, the hypervariable domain and aspartic acid 150, one of which has not previously been linked to the function of Rho GTPases. In addition, we show an unexpected dependence of Rac1 localization on Rac2 activity in these same cells, demonstrating a degree of crosstalk between two closely related Rho GTPases. Thus, we have defined specific sequences in Rac that specify subcellular localization and determine the specificity of Rac2 in neutrophil chemotaxis and superoxide generation.

Actins↗
PubMed1980

[Potassium, magnesium, copper, manganese and cobalt salts of aspartic acid on platelet factor 3 availability (author's transl)].

Inzolen, a combination of the potassium, magnesium, copper, manganese and cobalt salts of aspartic acid, inhibits the second phase of ADP-induced aggregation probably by affecting the membrane-located adenylatecyclase/phosphodiesterase system. Correspondingly inzolen affects the activation of platelet factor 3 (PF3), which is also located in the platelet membrane. Thus spontaneous as well as kaolin-induced platelet factor availability is reduced by inzolen. The significant inhibition of factor 3 availability can be interpreted by a magnesium-mediated activation of phosphoryltransferases.

Aspartic Acid↗
PubMed1996

Kainic acid, AMPA, and dihydrokainic acid effect on uptake and efflux of D-[3H] aspartic acid in cerebellar slices.

In this study we show that the glutamate ionotropic agonist kainate (KA) stimulates the efflux of preloaded D-[3H]aspartate (D-[3H]Asp) and inhibits the uptake of this amino acid in cerebellar slices. The effect of this agonist on the efflux of D-[3H]Asp is sensitive to (i) 6-nitro-7-sulphamoylbenzo(f)quinoxaline-2-3-dione (NBQX), indicating the involvement of KA/(RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, and is (ii) partially tetrodotoxin (TTX)-sensitive, indicating that pre-(TTX-insensitive) and post-synaptic (TTX-sensitive) KA/AMPA receptors are involved. In contrast, the effect on uptake is NBQX- and TTX-insensitive indicating a direct interaction with glutamate transporters. AMPA inhibited D-[3H]Asp uptake and had no effect on D-[3H]Asp efflux. In the same system, the uptake but not the efflux of D-[3H]Asp was affected by dihydrokainate (DHK). The DHK-induced uptake inhibition occurred in the presence of TTX. NBQX inhibited DHK-induced effect at 5 mM but not at 1 mM DHK concentrations.

Animals↗
PubMed1972

Replacement of asparagine by aspartic acid in hen ovalbumin and a difference in immunochemical reactivity.

Two forms of hen ovalbumin that exist as genetic variants were compared by physical and immunochemical techniques. The two ovalbumins could be distinguished by electrophoretic mobility and by antisera that had been pretreated with heterologous antigen. Peptide ;maps' of chymotrypsin digests of the two ovalbumins revealed that three of the peptides were different. These were isolated and analysed. One form of ovalbumin (type B) contains the sequence: -Ser-Ser-Ala-Asp-Leu-Ser-Gly-Ile-Ala-Glu-Ser(Ser,Leu)- whereas the other form (type A) contains an asparagine residue in place of the aspartic acid residue. The -Asn-Leu-Ser- sequence of type A is not glycosylated. Chymotrypsin readily cleaved the leucine-serine bond in the asparagine-containing peptide, but not in the aspartic acid-containing variant.

Amino Acid Sequence↗
PubMed2005

Recognition of benztropine by the dopamine transporter (DAT) differs from that of the classical dopamine uptake inhibitors cocaine, methylphenidate, and mazindol as a function of a DAT transmembrane 1 aspartic acid residue.

Binding of cocaine to the dopamine transporter (DAT) protein blocks synaptic dopamine clearance, triggering the psychoactive effects associated with the drug; the discrete drug-protein interactions, however, remain poorly understood. A longstanding postulate holds that cocaine inhibits DAT-mediated dopamine transport via competition with dopamine for formation of an ionic bond with the DAT transmembrane aspartic acid residue D79. In the present study, DAT mutations of this residue were generated and assayed for translocation of radiolabeled dopamine and binding of radiolabeled DAT inhibitors under identical conditions. When feasible, dopamine uptake inhibition potency and apparent binding affinity K(i) values were determined for structurally diverse DAT inhibitors. The glutamic acid substitution mutant (D79E) displayed values indistinguishable from wild-type DAT in both assays for the charge-neutral cocaine analog 8-oxa-norcocaine, a finding not supportive of the D79 "salt bridge" ligand-docking model. In addressing whether the D79 side chain contributes to the DAT binding sites of other portions of the cocaine pharmacophore, only inhibitors with modifications of the tropane ring C-3 substituent, i.e., benztropine and its analogs, displayed a substantially altered dopamine uptake inhibition potency as a function of the D79E mutation. A single conservative amino acid substitution thus differentiated structural requirements for benztropine function relative to those for all other classical DAT inhibitors. Distinguishing the precise mechanism of action of this DAT inhibitor with relatively low abuse liability from that of cocaine may be attainable using DAT mutagenesis and other structure-function studies, opening the door to rational design of therapeutic agents for cocaine abuse.

Amino Acid Substitution↗
PubMed1982

Phase I-phase II trial of N-phosphonacetyl-L-aspartic acid given by intravenous infusion and 5-fluorouracil given by bolus injection.

A phase I clinical trial of N-phosphonacetyl-L-aspartic acid (PALA) and 5-fluorouracil (FUra) was performed on 30 patients. PALA was given as a 15-minute iv infusion once daily for 5 days, and FUra was given as a bolus injection on days 2, 3, 4, and 5. Cycles of treatment were repeated every 3 weeks. Dose-limiting toxicity was manifested by stomatitis and diarrhea. Skin rash was observed also but was not dose limiting. No consistent hematopoietic or renal toxicity was observed. Seventeen patients with disseminated metastatic melanoma and measurable disease were evaluated for response. One partial response was seen; however, the response was associated with significant toxicity, and the treatment could not be repeated. Stable disease was observed in 3 patients with melanoma, 1 patient with colon carcinoma, and 1 patient with ovarian carcinoma. Our findings suggest that the clinical activity of PALA and FUra given according to the above schedule for melanoma is less than 25% (P less than 0.05). Pharmacokinetic studies of FUra revealed no consistent effect of PALA pretreatment on FUra disappearance in plasma. The mean FUra elimination half-line in plasma was 7.11 +/- 0.84 minutes (SEM), which is no different from that reported for FUra alone. The recommended doses on this schedule for phase II studies are 1,000 mg PALA/m2/day iv daily for 5 days and 200 mg FUra/m2/day iv on days 2, 3, 4, and 5.

Adult↗
PubMed1988

Chemical cross-linking of arginyl-glycyl-aspartic acid peptides to an adhesion receptor on platelets.

A chemical cross-linking approach has been used to characterize the interaction of platelets with small peptides of 7 and 14 residues containing the arginyl-glycyl-aspartic acid (RGD) sequence recognized by a variety of cellular adhesion receptors. The radioiodinated peptides were bound to platelets, and chemical cross-linking was attained by subsequent addition of bifunctional reagents. Three different cross-linking reagents coupled the RGD-containing peptides to platelet membrane glycoprotein IIb-IIIa (GPIIb-IIIa), and both subunits of this platelet membrane glycoprotein became radiolabeled with the RGD peptides. Platelet stimulation with agonists including thrombin, phorbol myristrate acetate, and ADP increased the extent of cross-linking by predominantly enhancing the coupling of the RGD peptides to the GPIIIa subunit. Cross-linking of the labeled RGD peptides to GPIIb and GPIIIa on stimulated and nonstimulated platelets exhibited structural specificity and was inhibited by excess nonlabeled RGD peptides. The interactions were inhibited by nonlabeled RGD peptides and a peptide with an amino acid sequence corresponding to the carboxyl terminus of the gamma chain of fibrinogen but less effectively by an arginyl-glycyl-glutamic acid peptide. Cross-linking of the RGD peptides to GPIIb-IIIa was divalent ion-dependent and, on stimulated platelets, was inhibited by the adhesive proteins fibrinogen and fibronectin, but not by albumin. These results indicate that the RGD-binding sites on platelets reside in close proximity to both subunits of GPIIb-IIIa and that platelet stimulation alters the topography of these sites such that the peptides become more efficiently cross-linked to GPIIIa.

Amino Acid Sequence↗
PubMed2004

HLA-DRB1 alleles encoding the "shared epitope" are associated with susceptibility to developing rheumatoid arthritis whereas HLA-DRB1 alleles encoding an aspartic acid at position 70 of the beta-chain are protective in Mexican Mestizos.

The risk to develop rheumatoid arthritis (RA) has been associated with the presence of HLA-DRB1 alleles encoding the "shared epitope" (SE). Additionally, HLA-DRB1 alleles encoding an aspartic acid at position 70 (D70+ ) have been associated with protection against the development of RA. In this study we tested the association between either SE or D70+ and rheumatoid arthritis in Mexican Mestizos. We included 84 unrelated Mexican Mestizos patients with RA and 99 unrelated healthy controls. The HLA-typing was performed by PCR-SSO and PCR-SSP. We used the chi-squared test to detect differences in proportions of individuals carrying at least one SE or D70+ between patients and controls. We found that the proportion of individuals carrying at least one HLA-DRB1 allele encoding the SE was significantly increased in RA cases as compared to controls (p(c) = 0.0004, OR = 4.1, 95% CI = 2.2-7.7). The most frequently occurring allele was HLA-DRB1*0404 (0.161 vs 0.045). Moreover, we observed a significantly increased proportion of HLA-DRB1 SE+ cases with RF titers above the median (p = 0.005). Conversely, the proportion of individuals carrying at least one HLA-DRB1 allele encoding the D70+ was significantly decreased (p(c) = 0.004, OR = 0.4, 95% CI 0.2-0.7) among RA patients compared with controls. In conclusion, the SE is associated with RA in Mexican Mestizos as well as with the highest titers of RF.

Adult↗
PubMed1987

[Effects of aspartic acid in the electroreceptors of the skate].

To identify the afferent transmitter in ampullary electroreceptors of the marine skates effects of L-aspartic acid (L-ASP) were examined using bath application of the drug. Perfusion of the basal membrane with L-ASP produced an increase in activity in most experiments (threshold concentrations 10(-7) M). L-GLU and L-ASP were identical in their ability to activate the afferents. In the presence of presynaptic blockade (high Mg2+) bath application of L-ASP restored the resting activity, suggesting a postsynaptic action of L-ASP. The results are consistent with the view that L-GLU, L-ASP or a related compound may play a role in afferent transmission in the ampullae of Lorenzini of skates.

Action Potentials↗
PubMed2000

Enzymatic synthesis of L-[4-13C]aspartic acid.

An efficient procedure for the production of l-[4-13C]aspartic acid (4-13C-Asp) was investigated. In this procedure, phosphoenolpyruvate carboxylase originating from the methanol-assimilating microbe, Methylobacterium extorquens JCM 2805, was used for the production of labeled oxaloacetic acid from phosphoenolpyruvate (PEP) and NaH13CO3; the oxaloacetic acid was then converted to 4-13C-Asp with glutamic-oxaloacetic transaminase. In this reaction, with starting concentrations of 10 mM PEP, 10 mM NaH13CO3 and 15 mM L-glutamic acid (Glu), the yield was 70%. 4-13C-Asp and Glu in the final reaction mixture were separated by displacement chromatography. The yield of this process was 84%. The overall yield was 59%. The incorporation of 13C at the C-4 position of 4-13C-Asp was confirmed by NMR spectroscopy.

Journal Article↗
PubMed1979

Determination of N-(Phosphonacetyl)-L-aspartic acid (PALA) in dog serum and urine by gas chromatography and selected lon monitoring.

Methods are described for quantitating N-(phosphonacetyl)L-aspartic acid (PALA), a new antitumor agent presently undergoing clinical evaluation. These methods were developed to measure this compound in serum by gas chromatography using the selectivity of a nitrogen-phosphorus detector and in serum and urine by the gas chromatographic/mass spectrometric technique of selected ion monitoring. PALA and the internal standard, N-(phosphonacetyl)-L-glutamic acid (HOMOPALA), were analyzed as their tetramethyl derivatives. Extraction from the biologic fluids was achieved by first precipitating the protein with acetone and then drying the serum with subsequent washes of acetone and diethyl ether. PALA and HOMOPALA were than extracted from the dried serum into an anhydrous HCL/methanol/tetrahydrofuran solution. After removing the solvent, the extract was reacted with diazomethane to form the tetramethyl derivatives. The feasibility of the method was demonstrated in the dog by comparing the total radioactivity with PALA equivalents determined in blood and urine samples following iv administration of PALA-14C. The range of the analysis was 20.0--200 microgram/ml for the urine samples and 0.5--15 microgram/ml for the serum samples.

Animals↗
PubMedDate not supplied

Initial clinical study with N-(phosphonacetyl)-L-aspartic acid (PALA) in patients with advanced cancer.

Thirty-seven patients with inoperable malignancies were given 75 courses of N-(phosphonaceteyl)-L-aspartic acid (PALA). Twenty-seven of these patients received PALA as a continuous iv infusion over 24 hours at dose levels ranging from 500 to 10,500 mg/m2 of estimated body surface area. In addition, ten patients were given PALA by continuous iv infusion over 120 hours at total doses ranging from 4000 t0 8700 mg/m2. The dose-limiting toxic effects occurred in the skin (erythema, vesiculation, and bullae) and gastrointestinal mucosa (oral pain, cheilosis, oral mucosal ulceration, diarrhea, and hematochezia). Toxic reactions seemed more pronounced in patients with third-space fluid compartments. Myelosuppression was severe only in patients with pre-existing marrow dysfunction from neoplastic infiltration. No renal, hepatic, cardiac, or neurologic toxicity was seen. No cumulative toxic effects were evident in 14 patients who received repeated courses of PALA at 21-day intervals. For patients without third-space fluid, 8700 mg/m2/24 hours or 6500 mg/m2/120 hours were well-tolerated doses. One patient with chondrosarcoma had a partial response lasting 5 months.

Adult↗
PubMed1999

Evidence for a direct interaction between the penultimate aspartic acid of cholecystokinin and histidine 207, located in the second extracellular loop of the cholecystokinin B receptor.

Recently, we reported that the mutation of His(207) to Phe located in the second extracellular loop of the cholecystokinin B receptor strongly affected cholecystokinin (CCK) binding (Silvente-Poirot, S., Escrieut, C., and Wank, S. A. (1998) Mol. Pharmacol. 54, 364-371). To characterize the functional group in CCK that interacts with His(207), we first substituted His(207) to Ala. This mutation decreased the affinity and the potency of CCK to produce total inositol phosphates 302-fold and 456-fold without affecting the expression of the mutant receptor. The screening of L-alanine-modified CCK peptides to bind and activate the wild type and mutant receptors allowed the identification of the interaction of the C-terminal Asp(8) of CCK with His(207). The H207A-CCKBR mutant, unlike the wild type receptor, was insensitive to substitution of Asp(8) of CCK to other amino acid residues. This interaction was further confirmed by mutating His(207) to Asp. The affinity of CCK for the H207D-CCKBR mutant was 100-fold lower than for the H207A-CCKBR mutant, consistent with an electrostatic repulsion between the negative charges of the two interacting aspartic acids. Peptides with neutral amino acids in position eight of CCK reversed this effect and displayed a gain of affinity for the H207D mutant compared with CCK. To date, this is the first report concerning the identification of a direct contact point between the CCKB receptor and CCK.

Amino Acid Sequence↗