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PubMed1996

Aspartic acid conjugates of 2-(3,4-dichlorophenyl)-N-methyl-N-[(1S)-1(3-aminophenyl)-2-(1-pyrrolidi nyl) ethyl]acetamide: kappa opioid receptor agonists with limited access to the central nervous system.

Aspartic acid conjugates of 2-(3,4-dichlorophenyl)-N-methyl-N-[(1S)-1-(3-aminophenyl)-2-(1-pyrrol idinyl) ethyl]acetamide (5) were synthesized and evaluated in mice for antinociceptive activity by intravenous and intracerebroventricular routes of administration. The intravenously-administered alpha-conjugate of L-Asp (2), its D-Asp diastereomer (3), and the beta -conjugate of L-Asp (4) were found to be 11-, 31-, and 40-fold, respectively, less effective than the parent ligand 1 (ICI 199,441) in producing central nervous system mediated antinociception in the mouse abdominal stretch assay. In addition, iv-administered 2 and 3 were found to also produce potent antinociception in the tonic phase of the mouse formalin assay, which is a model of tonic rather than acute pain. This study suggests that the attachment of a zwitterionic moiety to a position in the molecule that exhibits bulk tolerance is a viable strategy for the design of peripherally-selective and peripherally-active opioids.

Animals↗
PubMed1992

Phase I study of high dose 5-fluorouracil and high dose Leucovorin with low dose phosphonacetyl-L-aspartic acid in patients with advanced malignancies.

Twenty-eight patients with refractory advanced malignancies were treated with a 24 hr infusion of 5-fluorouracil (5-FU), Leucovorin (LV), and N-(phosphonacetyl)-L-aspartic acid (PALA) weekly. Twenty-seven patients were evaluable for the assessment of toxicity and anti-tumor activity. PALA was administered as intravenous bolus over 15 min at a fixed dose, 250 mg/m2 24 hr before the start of 5-FU and LV infusions. 5-FU was initially administered at 750 mg/m2 and was incrementally increased to 2600 mg/m2. LV was administered in a fixed dose of 500 mg/m2 concurrently with 5-FU over a 24-hr period. The course was repeated weekly. Diarrhea, stomatitis, nausea, and vomiting were among dose-limiting toxic effects. Other toxicities observed were hand-foot syndrome, hair loss of scalp/eyelashes, overall weakness, rhinitis, and chemical conjunctivitis. Maximum tolerated dose (MTD) of 5-FU in this combination and schedule was 2600 mg/m2. Seven of 14 patients treated at 2600 mg/m2 were able to tolerate the chemotherapy on a weekly basis without interruption. The other seven patients required dose de-escalation, a majority of whom contained 5-FU at a dose of 2100 mg/m2. Twenty-three of 27 patients had been previously treated. Eight patients achieved a partial response, all of whom were previously treated, except three patients. A complete response was observed in a patient with pancreatic carcinoma, previously untreated. Overall response rate for the patients who were treated at the 5-FU dose of 2100 mg/m2 or 2600 mg/m2 is 9 of 18 patients (50%).

Adult↗
PubMed1989

N-methyl-aspartic acid lesions of the arcuate nucleus in adult C57BL/6J mice: a new model for age-related lengthening of the estrous cycle.

We report a new effect of the excitotoxin N-methyl-aspartic acid (NMA) on adult mice. Besides confirming cell loss in the arcuate nucleus of animals treated as adults, we also observed lengthened estrous cycles. Cycling female C57BL/6J mice were treated with subcutaneous injections of NMA and estrous cycles monitored for 30 days. NMA treatment lengthened average estrous cycle length by 1 day, to 5.6 days. The elongated cycles were due to an increase in the frequency of 5- and 6-day cycles at the expense of 4-day cycles. This effect was observed in mice aged 4 and 7 months; however, 10-month-old mice had irregular cycles and a higher mortality rate following NMA, which precluded cycle analysis. NMA caused a region-specific 30-45% cell loss in the rostral portions of the arcuate nucleus; no cell loss was detected in the adjacent ventromedial nucleus. Possible neuronal substates for NMA lesions, as analyzed by in vitro receptor autoradiography for glutamate receptor subtypes, include a high density of kainate receptors in the arcuate nucleus; there was little specific binding of ligands to NMDA and quisqualate receptors. Consistent with the regional pattern of cell loss, little specific binding of any glutamatergic ligand was observed in the VMN. NMA caused weight gain in all age groups. Serum LH and PRL were unaffected by NMA. The transition from 4-day to 5- and 6-day estrous cycles produced by NMA treatment mimics the early age-related changes in estrous cycle patterns in rodents. This new model will be useful in analyzing the contributions of neuroendocrine changes in the arcuate nucleus to reproductive senescence.

Aging↗
PubMed1991

A phase I, II study of high-dose 5-fluorouracil and high-dose leucovorin with low-dose phosphonacetyl-L-aspartic acid in patients with advanced malignancies.

Twenty-eight patients with refractory advanced malignancies were treated with a 24-hour infusion of 5-fluorouracil (5-FU), leucovorin (LV), and N-(phosphonacetyl)-L-aspartic acid (PALA) weekly. Twenty-seven patients were evaluable to assess toxicity and antitumor activity. The PALA was administered as an intravenous bolus over 15 minutes at a fixed dose (250 mg/m2) 24 hours before the start of the 5-FU and leucovorin infusions. Initially the dose of 5-FU was 750 mg/m2; this was increased incrementally to 2600 mg/m2. The LV was administered in a fixed dose of 500 mg/m2 concurrently with the 5-FU over a 24-hour period. This regimen was repeated weekly. Diarrhea, stomatitis, nausea, and vomiting were among the dose-limiting toxicities. Others were hand-foot syndrome, hair loss of the scalp and eyelashes, overall weakness, rhinitis, and chemical conjunctivitis. The maximum tolerated dose of 5-FU in this combination and schedule was 2600 mg/m2. Seven of 14 patients treated with 2600 mg/m2 were able to tolerate the chemotherapy on a weekly basis without interruption. The other seven patients required dose reductions, but most received 5-FU at a dose of 2100 mg/m2. Twenty-three of 27 patients were treated previously. Eight patients had a partial response; five of these were treated previously. A complete response was observed in one patient with pancreatic carcinoma, previously untreated. The overall response rate for patients treated with 2100 or 2600 mg/m2 of 5-FU was nine of 18 patients (50%). Three of four previously untreated patients with pancreatic cancer responded to this treatment (two responded partially, and one had a complete response). One of three heavily pretreated patients with non-small cell lung cancer had a partial response as did a patient with breast cancer. Four of ten patients with colorectal cancer responded to the treatment (four partial responses), of whom three had been treated previously.

Adult↗
PubMed2003

Direct enantiomeric resolution of (+/-)-atenolol, (+/-)-metoprolol, and (+/-)-propranolol by impregnated TLC using L-aspartic acid as chiral selector.

Resolution of three commonly used beta-blockers, (+/-)-atenolol, (+/-)-metoprolol and (+/-)-propranolol, into their enantiomers has been achieved using normal-phase TLC on silica gel plates impregnated with L-aspartic acid as the chiral selector. Different combinations of acetonitrile-methanol-water as mobile phase were found to be successful in resolving the enantiomers. The spots were detected with iodine and the detection limits were found to be 0.26 microg for atenolol and 0.23 microg for each of metoprolol and propranolol as racemate.

Adrenergic beta-Antagonists↗
PubMed2004

Phospho-N-acetyl-muramyl-pentapeptide translocase from Escherichia coli: catalytic role of conserved aspartic acid residues.

Phospho-N-acetyl-muramyl-pentapeptide translocase (translocase 1) catalyzes the first of a sequence of lipid-linked steps that ultimately assemble the peptidoglycan layer of the bacterial cell wall. This essential enzyme is the target of several natural product antibiotics and has recently been the focus of antimicrobial drug discovery programs. The catalytic mechanism of translocase 1 is believed to proceed via a covalent intermediate formed between phospho-N-acetyl-muramyl-pentapeptide and a nucleophilic amino acid residue. Amino acid sequence alignments of the translocase 1 family and members of the related transmembrane phosphosugar transferase superfamily revealed only three conserved residues that possess nucleophilic side chains: the aspartic acid residues D115, D116, and D267. Here we report the expression and partial purification of Escherichia coli translocase 1 as a C-terminal hexahistidine (C-His6) fusion protein. Three enzymes with the site-directed mutations D115N, D116N, and D267N were constructed, expressed, and purified as C-His6 fusions. Enzymatic analysis established that all three mutations eliminated translocase 1 activity, and this finding verified the essential role of these residues. By analogy with the structural environment of the double aspartate motif found in prenyl transferases, we propose a model whereby D115 and D116 chelate a magnesium ion that coordinates with the pyrophosphate bridge of the UDP-N-acetyl-muramyl-pentapeptide substrate and in which D267 therefore fulfills the role of the translocase 1 active-site nucleophile.

Amino Acid Sequence↗
PubMed2002

Effect of sucrose on formation of the beta-amyloid fibrils and D-aspartic acids in Abeta 1-42.

Beta-amyloid peptide 1-42 is a major peptide constituent of beta-amyloid fibrils. We investigated the role of sucrose on the deposition and the D-aspartic acid formation in an amyloidogenic peptide 1-42 under physiological conditions. From analyses using thioflavine-T fluorometric assay and electronmicroscopic spectroscopy after 60 h incubation at 37 degrees C, it was found that sucrose retarded the fibril formation in the amyloidogenic peptide. The retardation of the formation of amyloid fibrils by sucrose was suggested to be not due to viscosity but due to disturbance of the assemlby of alpha-helix containing peptides. Moreover, we showed that the formation of D-aspartyl residue, which is found in beta-amyloid fibrils from Alzheimer disease brains, in the amyloidogenic peptide was also retarded in the presence of sucrose.

Amyloid beta-Peptides↗
PubMed1994

Age estimation by aspartic acid racemization in dentin of deciduous teeth.

In forensic dental medicine, one of the most important endeavors is the estimation of age. We have studied the method of age assessment using the D/L ratio of aspartic acid from the dentin. The age of deciduous teeth has been estimated by measuring the racemization reaction of this amino acid. The results of the present study indicated that the measured D/L ratio for the dentin of deciduous teeth was highly correlated with the real age (r = 0.824 - 0.981 (sigma = +/- 0.5 to +/- 1.3). These results indicate that age can be accurately estimated from the dentin of deciduous teeth, as it can when permanent teeth are used, and that the D/L ratio is more highly correlated with age than is the eruption time of permanent teeth.

Adolescent↗
PubMed2006

Comparison of aspartic acid racemization between mammoth and human dentinal tissues.

OBJECTIVE: Comprehensive research has revealed the complexity and heterogeneity of amino acid racemization (AAR) in biological samples. Therefore, to date, inherent uncertainties in relative dating as well as in determination of age at death have highlighted the significance of further investigations to explore aspartic acid kinetics in biominerals. Here we present data on an archaeological sample obtained from a mammoth tusk, in comparison to a previously well-described biomineral, to modern human dentin. DESIGN: Since no experimental investigations were carried out on this topic earlier, we provide the first estimates on racemization kinetics and time dependent tendencies in mammoth dentin. We analysed our samples using a protocol, which has been adopted for tooth dentin investigation. We measured different racemization rates amongst mammoth dentin layers. RESULTS AND CONCLUSIONS: Significantly, an overall low racemization rate was detected compared to human dentin. Kinetic experiments were performed by heating the samples, and linear correlations were established between racemization rates and heating time. The results allow us to derive racemization rate constants and activation energy for both samples. Extrapolation for ambient temperature showed increased velocity in mammoth dentin, which can be explained by biodeterioration of ancient collagen and by diagenetic changes in amino acid composition influenced by environmental conditions.

Animals↗
PubMed1997

Aspartic acid 252 and asparagine 185 are essential for activity of lipid N-acetylglucosaminylphosphate transferase.

A key step in the assembly of oligosaccharide-lipid intermediates in N-linked glycosylation is the transfer of N-acetylglucosamine 1-phosphate to dolichyl phosphate, catalyzed by the enzyme UDP-N-acetylglucosaminyl:dolichyl phosphate N-acetylglucosaminyl phosphoryl transferase (L-G1PT). Comparison of the amino acid sequences of L-G1PT from five diverse species showed 75 amino acids identical in all five proteins. Using site-directed mutagenesis, we analyzed the importance of a number of these conserved residues to the enzymatic activity of L-G1PT using a plasmid shuffling procedure in Schizosaccharomyces pombe. S. pombe cells containing a chromosomal deletion of the essential gpt+ gene are rescued by a plasmid containing the S. pombe gpt open reading frame. Replacement of that plasmid by a plasmid encoding a mutated hamster L-G1PT cDNA sequence indicated that the mutated protein provided sufficient enzyme activity to permit cell growth. Mutations of aspartic acid 252 and asparagine 185 did not allow plasmid shuffling, indicating these residues were essential for activity. A combination of mutations at asparagine 182 and tryptophan 122 did not allow plasmid shuffling, although the single mutations did. Overexpression of the mutant proteins in S. pombe conferred tunicamycin (TM) resistance, indicating that the mutant proteins had a conformation necessary for binding TM, a substrate analog. The mutant proteins were also detected in Western blots and were correctly localized to the membrane fractions. However, the overexpressed proteins did not increase the endogenous level of enzymatic activity in these cells, indicating they were enzymatically inactive.

Alleles↗
PubMed1998

Contribution of the absence of aspartic acid at position 57 of the HLA-DQ beta chain to predisposition to insulin-dependent diabetes mellitus in a southern Chinese population.

OBJECTIVE: To investigate the association of the absence or presence of aspartic acid at position 57 of the HLA-DQ beta chain (NA or A) with susceptibility or resistance to insulin-dependent diabetes mellitus (IDDM) in a Southern Chinese population. METHODS: Sixty-nine IDDM patients and 47 healthy controls in a Southern Chinese population were HLA-DQB1 genotyped by one-step sequence specific polymerase chain reaction (ssPCR). RESULTS: The frequencies of NA and A were 64.5% and 35.5% in the IDDM patients, and 40.4% and 59.6% in the control subjects respectively (RR for NA was 2.68, P < 0.01). The frequencies of NA/NA, NA/A and A/A phenotypes were 47.8%, 33.3% and 18.8% in the IDDM patients, and 31.9%, 17.0% and 51.1% in the controls respectively (P < 0.01). The frequency of A/A phenotype was significantly lower in the IDDM patients than in the control subjects (RR = 0.22, P < 0.01). DQB1* 0302 and DQB1* 0201 were more frequent in IDDM patients than in control subjects. The younger the age of IDDM onset, the higher the allele frequencies of DQB1* 0201 and DQB1* 0302. CONCLUSION: The present study suggests that the NA confers the susceptibility to IDDM, while the A confers the protection against IDDM in patients of Southern Chinese origin. These associations are more clearcut in childhood-onset IDDM patients.

Adolescent↗
PubMed1996

Direct measurement of the aspartic acid 26 pKa for reduced Escherichia coli thioredoxin by 13C NMR.

Because of interference from the pH-dependent behavior of nearby groups in the active site of Escherichia coli thioredoxin, the pKa of the buried carboxyl group of the aspartic acid at position 26 has been difficult to quantitate. We report a direct measurement of this pKa using an NMR method utilizing the correlation between the C beta H proton resonances and the 13CO of the titrating carboxyl group. The experiments show unequivocally that the pKa is 7.3-7.5, rather than the value of 9 or greater recently proposed by Wilson, N. A., et al. [(1995) Biochemistry 34, 8931-8939]. The assignment of the titrating resonances to Asp 26 is unambiguous: the values of the C beta H chemical shifts correspond exactly to those of Asp 26, and their titration in the pH range 5.7-10.0 is the same as that observed previously for the proton resonances alone. In addition, the chemical shift of the carboxyl 13C resonance at pH 5.7 is upfield of those of the other carboxyl and carboxamide resonances, diagnostic for a protonated carboxyl group. The resonances assigned to Asp 26 are the only ones that titrate in the pH range 5.7-10.5. None of the other aspartate and glutamate residues in the molecule are titrated in this pH range, consistent with their positions on the surface of the molecule. The pKa measured for Asp 26 in reduced thioredoxin is identical within experimental error to that measured in the oxidized form of the protein. This is significant for the reductive mechanism of thioredoxin: the buried salt bridged/hydrogen-bonded side chains of Asp 26 and Lys 57 are likely to contribute to the facility of the reaction by providing a convenient source and sink for protons in the hydrophobic environment of the complex between thioredoxin and its substrates.

Amino Acid Sequence↗
PubMed1990

Glutamate receptors of the non-N-methyl-D-aspartic acid type mediate the increase in luteinizing hormone-releasing hormone release by excitatory amino acids in vitro.

The present study was designed to analyze in detail the effects of L-glutamate (L-Glu) and its agonists on the release of LHRH from arcuate nucleus-median eminence (AN-ME) fragments in vitro. Fragments from adult male rats were incubated in Krebs-Ringer bicarbonate buffer in the presence of different concentrations of L-Glu, kainate (KA), N-methyl-D-aspartic acid (NMDA), and quisqualate (QA). L-Glu at 10-20 mM evoked a significant increase in basal LHRH release, while D-glutamate at similar concentrations was ineffective. Partial depolarization with 14 mM K+ significantly augmented the release of LHRH induced by L-Glu. L-Glu-induced LHRH release was blunted in a dose-related manner by the specific KA/QA receptor antagonist 6,7-dinitroquinoxaline-2,3-dione. Exposure to KA or QA significantly increased LHRH release at concentrations (1 mM) much lower than those required for L-Glu. In the presence of 14 mM K+ the potencies of KA and QA (0.075 and 0.1 mM, respectively) were significantly enhanced. 6,7-Dinitroquinoxaline-2,3-dione blocked KA-induced LHRH release, while AP-7, a competitive NMDA receptor antagonist, was inactive in preventing L-Glu- and KA-induced LHRH release. LHRH secretion from AN-ME fragments was unaffected by NMDA at concentrations up to 10 mM in the different media tested. A significant stimulatory effect of NMDA at 20 mM was observed when fragments were incubated in Mg2+-free medium. These results show the stereoselectivity of L-Glu to enhance LHRH release from AN-ME fragments in vitro. Moreover, in view of the respective potencies of excitatory amino acid agonists (KA = QA greater than L-Glu greater than NMDA) and the selective antagonism of excitatory amino acid effects, they provide evidence that non-NMDA receptors primarily mediate the excitatory actions of L-Glu on LHRH release from nerve terminals in the AN-ME.

Amino Acids↗
PubMed1987

Analysis of aspartic acid racemization. Evaluation of a chiral capillary gas chromatographic and a diastereomeric high-performance liquid chromatographic method.

A recently developed chiral gas chromatographic method and a diastereomeric high-performance liquid chromatographic method for the analysis of aspartic acid enantiomers in protein hydrolyzates have been evaluated. Although both techniques are fast and convenient, the latter is preferred because of its higher reproducibility and shorter analysis time. Furthermore, this method offers the possibility of on-line derivatization and analysis.

Aspartic Acid↗
PubMed1999

Aspartic acid for asparagine substitution at position 276 reduces susceptibility to mechanism-based inhibitors in SHV-1 and SHV-5 beta-lactamases.

In SHV-type beta-actamases, position 276 (in Ambler's numbering scheme) is occupied by an asparagine (Asn) residue. The effect on SHV-1 beta-lactamase and its extended-spectrum derivative SHV-5 of substituting an aspartic acid (Asp) residue for Asn276 was studied. Mutations were introduced by a PCR-based site-directed mutagenesis procedure. Wild-type SHV-1 and -5 beta-lactamases and their respective Asn276-->Asp mutants were expressed under isogenic conditions by cloning the respective bla genes into the pBCSK(+) plasmid and transforming Escherichia coli DH5alpha. Determination of IC50 showed that SHV-1(Asn276-->Asp), compared with SHV-1, was inhibited by 8- and 8.8-fold higher concentrations of clavulanate and tazobactam respectively. Replacement of Asn276 by Asp in SHV-5 beta-lactamase caused a ten-fold increase in the IC50 of clavulanate; the increases in the IC50s of tazobactam and sulbactam were 10- and 5.5-fold, respectively. Beta-lactam susceptibility testing showed that both Asn276-->Asp mutant enzymes, compared with the parental beta-lactamases, conferred slightly lower levels of resistance to penicillins (amoxycillin, ticarcillin and piperacillin), cephalosporins (cephalothin and cefprozil) and some of the expanded-spectrum oxyimino beta-lactams tested (cefotaxime, ceftriaxone and aztreonam). The MICs of ceftazidime remained unaltered, while those of cefepime and cefpirome were slightly elevated in the clones producing the mutant beta-lactamases. The latter clones were also less susceptible to penicillin-inhibitor combinations. Asn276-->Asp mutation was associated with changes in the substrate profiles of SHV-1 and SHV-5 enzymes. Based on the structure of TEM-1 beta-lactamase, the potential effects of the introduced mutation on SHV-1 and SHV-5 are discussed.

Amino Acid Substitution↗
PubMed1992

N-methyl-D-aspartic acid injected peripherally stimulates oxytocin and vasopressin release.

The effects of N-methyl-D-aspartic acid (NMDA), injected s.c. or i.p. in the dose range of 2.5-10 mg/kg, on oxytocin and vasopressin levels were assessed in conscious rats. NMDA administration was found to induce a dose-related increase in oxytocin concentration with a peak response at 7.5 min. Plasma vasopressin was elevated only after injection of the highest dose used (10 mg/kg). Thus, though at different thresholds, the release of both posterior pituitary hormones was stimulated after NMDA administration.

Animals↗
PubMed1994

Antiproliferative effect of D-aspartic acid beta-hydroxamate (DAH) on Friend virus-infected erythropoietic progenitor cells.

D-aspartic beta-hydroxamate (DAH), an aspartic acid analog, exerts antitumoral activity on murine leukemia L5178Y, both in vitro and in vivo. In this study, we show that DAH is also active in vivo against Friend virus (FV-P)-induced erythroleukemia, and we report the effects of DAH in vivo an in vitro on FV-P target cells, i.e. the mature erythroid colony-forming cells (CFU-E). DAH treatment (2 g/kg/day) given for 95 days as a single daily i.p. injection to DBA/2 mice either 3 or 12 days following inoculation with a high dose (10(3) plaque-forming units) of FV-P resulted in a marked increase in the mean survival time of treated animals (212 and 191%, respectively). Since FV-P elicits spleen enlargement and polycythemia, we examined the effects of DAH on spleen size, spleen-nucleated cell number, and hematocrit, in normal and FV-P infected mice, at different times in the course of continuous DAH treatments. DAH treatment initiated 3 days after viral infection inhibits the virus-induced splenomegaly, with at day 26 p.i. 1.15 x 10(8) and 12.6 x 10(8) nucleated cells per spleen observed in DAH-treated mice and untreated mice respectively, whereas only 1.03 x 10(8) nucleated cells were observed in uninfected mice. Furthermore, DAH prevents virus-induced polycythemia: on day 26, an hematocrit of 39% was measured in DAH-treated mice as compared to 60% in untreated mice. DAH treatment initiated 12 days after viral infection reduces splenomegaly, the number of nucleated spleen cells and the hematocrit of infected mice. DAH treatment initiated 3 days after viral infection prevents the tremendous increase of CFU-E in the spleen of infected mice: on day 11, the spleen of infected mice contained 4.6 x 10(6) CFU-E, while the spleen of treated mice only contained 26 x 10(3) CFU-E, and on day 26 the spleen CFU-E numbers were 45.4 x 10(6) and 1.5 x 10(6) in untreated and treated infected mice, respectively. In control uninfected mice, DAH treatment induced a transient decrease in spleen CFU-E followed by a rebound phenomenon. In vitro, preincubation with DAH inhibits colony formation by FV-P infected CFU-E, at doses starting at 3 mM, as compared to uninfected CFU-E. These data show that DAH inhibits the expression of the retroviral infection, and appears to preferentially inhibit the proliferation of infected target cells (CFU-E) in vivo.

Animals↗