[FURTHER CLINICAL AND BIOCHEMICAL VERIFICATIONS OF THE THERAPEUTIC ACTION OF ASPARTIC ACID IN CHRONIC HEPATITIS].
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Alanine Transaminase↗
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The effect of delta-aminolaevulinic acid on the high affinity uptake of aspartic acid by rat brain synaptosomes.
delta-Aminolaevulinic (delta-ALA) acid is an analogue of GABA, glutamate and aspartate. High affinity GABA uptake by synaptosomes is inhibited by delta-ALA in a competitive fashion at high concentrations (greater than 0.5 mM). Glutamate uptake is inhibited in a non-competitive fashion at all delta-ALA concentrations (0.05-2.0 mM). High affinity aspartate uptake is inhibited in a non-competitive fashion at high concentration (greater than 1.0 mM) but exhibits a curve which resembles that for the inhibition of GABA uptake. The different interactions between delta-ALA, glutamate and aspartate may be evidence for a separate transport system for aspartate.
Aminolevulinic Acid↗
Mechanism of resistance of variants of the Lewis lung carcinoma to N-(phosphonacetyl)-L-aspartic acid.
Variants of the Lewis lung carcinoma were selected for resistance to N-(phosphonacetyl)-L-aspartic acid (PALA) by treatment of tumor-bearing mice with repetitive subcurative doses of PALA. The specific activity of the target enzyme, L-aspartic acid transcarbamylase (ATCase), was measured in the four variants developed. Three had markedly elevated ATCase activities; however, the fourth line, LL/PALA-C, had an ATCase activity identical to that of the parent, PALA-sensitive line (LL/O). One high-ATCase variant, LL/PALA-J, and LL/PALA-C were compared with LL/O in subsequent biochemical studies on the mechanism of resistance to PALA. Enzyme activities in the salvage pathways which phosphorylate pyrimidine nucleosides and deoxynucleosides were found to be similar in all three lines. ATCase in these lines exhibits closely comparable kinetics with its natural substrates as well as with PALA. The time courses of restitution of ATCase after a single therapeutic dose of PALA show that both resistant variants recover full activity more rapidly than the parent. Additionally, inhibition of ATCase 24 hr following graded doses of PALA is lower in the resistant lines. The uptake of [14C]PALA in vitro into cell lines derived from the three Lewis lung carcinomas apparently occurs by passive diffusion and at comparable rates in both sensitive and resistant cells. Analysis of the nucleotide content of tumors reveals comparable spectrums of purine and pyrimidine nucleotide levels in the LL/O and LL/PALA-C lines, whereas the LL/PALA-J line has augmented nucleotide pools. In all three lines, 24 hr after treatment with PALA (400 mg/kg), uridine and cytidine nucleotide levels were substantially diminished (70 to 80%) while adenosine 5'-triphosphate and guanosine 5'-triphosphate levels were elevated (50 to 100%). Estimations of precursor flux through the de novo pyrimidine pathway by measuring orotate and orotidine levels in tumors of mice treated with pyrazofurin (an inhibitor of orotidine-5'-monophosphate decarboxylase) and either 0.9% NaCl solution or PALA shows that PALA treatment eliminates orotate and orotidine accumulation in LL/O but reduces it by only 75 and 50% in LL/PALA-C and LL/PALA-J, respectively. Similarly, PALA treatment (20 microM) of tumor lines in culture provokes a dramatic decrease in the incorporation of NaH14CO3 into pyrimidine intermediates and nucleotides in the LL/O cell line only. Determinations of specific activities of the other enzymes in this pathway reveal that the activity of carbamyl phosphate synthetase II, the rate-limiting step, is elevated 2- to 3-fold in both resistant lines. Since carbamyl phosphate synthetase II exists as a complex with ATCase, the suggestion is made that levels of carbamyl phosphate synthetase II are collaterally important determinants of PALA activity. An augmented pool of carbamyl phosphate in the resistant variants may serve to competitively displace PALA from ATCase, diminish enzyme inhibition, and allow pyrimidine biosynthesis to proceed despite therapy.
Amides↗
N-alkoxycarbonyl-glutamic and aspartic acids. Studies on the activation and cyclodehydration and side-reaction encountered in analysis of glutamic acid using Fmoc-chloride.
N-Alkoxycarbonylaminodicarboxylic acids were reacted in dichloromethane with N-ethyl-N'-(dimethylaminopropyl)carbodiimide hydrochloride, and with methyl chloroformate in the presence of N-methylmorpholine. Removal of secondary products by washing the mixtures with aqueous solutions gave good yields of the pure crystalline internal anhydrides. Anhydrides of N-benzyloxycarbonyl- (Z) and N-9-fluorenylmethoxycarbonyl-(Fmoc) L-glutamic and L-aspartic acids and of N-tert.-butoxycarbonyl-L-aspartic acid were prepared in this way. The compounds were shown to be amenable to normal phase high-performance liquid chromatography (NP-HPLC) on a CN-column using tert.-butanol-hexane as solvent. The products of the reactions of Z- and Fmoc-glutamic acid with hot acetic anhydride were examined by nuclear magnetic resonance and NP-HPLC before and after methanolysis in an attempt to establish if any of the corresponding pyroglutamates were formed. The reaction of Fmoc-chloride with Fmoc-glutamate was examined for the same reason. It is concluded that the side product generated during the reaction of Fmoc-chloride with glutamic acid which is used for analysis of the latter is the N-protected internal anhydride and not the pyroglutamate as reported in the literature.
Amino Acids↗
Interconversion between serine and aspartic acid in the alpha helix of the N-terminal zinc finger of Sp1: implication for general recognition code and for design of novel zinc finger peptide recognizing complementary strand.
In the typical base recognition mode of the C(2)H(2)-type zinc finger, the amino acid residues at alpha-helical positions -1, 3, and 6 make a contact with the base in one strand (the primary strand), and the residue at position 2 interacts with the base in a complementary strand (the secondary strand). The N-terminal zinc finger of the three-zinc-finger domain of Sp1 has inherently a unique five-base-pair binding mode in which the guanine bases are recognized in both strands. To clarify the effect of the amino acid at position 2 on DNA binding affinity and base specificity, we have created a library of the mutants by the interconversion between serine and aspartic acid in the N-terminal zinc finger of Sp1 and recombinant variants of finger order. Gel mobility shift and methylation interference assays showed that the combination of arginine and serine at positions -1 and 2, respectively, provides a newly strong guanine contact in the secondary strand and a higher binding affinity than that of wild-type Sp1. Of special interest are the facts that the mutant with lysine and aspartic acid at positions -1 and 2 in the alpha helix predominantly recognizes the bases in the secondary strand and that its DNA binding affinity is higher than that of the wild-type. The aspartic acid or serine at position 2 independently contributes to the DNA binding affinity and base specificity. The present results provide useful information for the design of a novel zinc finger protein with priority for the bases in the secondary strand.
Aspartic Acid↗
Spontaneous deamidation of a protein antibiotic, neocarzinostatin, at weakly acidic pH. Conversion to a homologous inactive preneocarzinostatin due to change of asparagine 83 to aspartic acid 83 accompanied by conformational and biological alterations.
The amide content of neocarzinostatin (NCS), an antitumor protein, has been determined by analysing asparagine and glutamine in the Pronase-aminopeptidase M digests of tetra-S-carboxymethyl-NCS and carboxyl-modified NCS (modified with a water-soluble carbodiimide and [14C]glycine methyl ester). Preneocarzinostatin (PRE) was separated and purified from a crude NCS preparation by CM-cellulose column chromatography. PRE was found to contain one mole less asparagine than NCS, and asparagine was deamidated to aspartic acid in PRE. A time-dependent conversion of NCS to PRE at pH 3.2 at 4 degrees or in 0.1 M acetic acid at 26 degrees was studied in two ways; first, by quantitative determination of NCS and PRE by CM-cellulose column chromatography and second, by following the release of free NH3 during dialysis in an air-tight container. Within experimental error, PRE was indistinguishable from NCS in amino acid content after acid hydrolysis, as well as in apparent molecular weight as determined by SDS-disc gel electrophoresis (10% acrylamide), and N- and C-terminal amino acid residues. Both NCS and PRE shared a common antigenicity as determined by Ouchterlony's agar diffusion method. Only a slight difference between the two in electrophoresis on a cellulose acetate membrane and on a peptide map of the tryptic digest was demonstrated. PRE, however, was completely devoid of biological activity. In addition to the chromatographic difference, a conformational difference was observed by CD spectroscopy, namely, an apparently looser structure of PRE was indicated by the shallowness of the trough in the 240-265 nm region. This interpretation was supported by the finding that digestions by Pronase were more extensive with PRE than with NCS. These results indicate an important role of the single asparagine residue (Asn 83) of NCS in the biological activity, which is evidently governed by the conformation.
Amino Acids↗
Changes in D-aspartic acid in human deciduous teeth with age from 1-20 years.
The racemization ration (D/L ratio) of aspartic acid in the dentin (collagen) of deciduous teeth was studied, using dentin of permanent teeth as a reference. D-aspartic acid in deciduous teeth was found to increase almost linearly with aging. The reaction velocity constant of racemization (kyr-1) in deciduous teeth (1.1915 x 10(-3)yr-1) was approximately double the value for permanent teeth (6.2550 x 10(-4)yr-1). The velocity of the racemization reaction was similar between deciduous teeth and permanent teeth in a dry state. The D/L ratio determined using transverse sections of deciduous teeth tended to be high in the crown and low in the root. The reaction velocity of racemization is considered to be affected to some extent by the tooth material, ambient temperature and salivary pH, but most importantly by physiologic resorption of deciduous teeth at the root associated with age.
Adolescent↗
Aspartic acid-484 of nascent placental alkaline phosphatase condenses with a phosphatidylinositol glycan to become the carboxyl terminus of the mature enzyme.
A carboxyl-terminal chymotryptic peptide from mature human placental alkaline phosphatase was purified by HPLC and monitored by a specific RIA. Sequencing and amino acid assay showed that the carboxyl terminus of the peptide was aspartic acid, representing residue 484 of the proenzyme as deduced from the corresponding cDNA. Further analysis of the peptide showed it to be a peptidoglycan containing one residue of ethanolamine, one residue of glucosamine, and two residues of neutral hexose. The inositol glycan is apparently linked to the alpha carboxyl group of the aspartic acid through the ethanolamine. Location of the inositol glycan on Asp-484 of the proenzyme indicates that a 29-residue peptide is cleaved from the nascent protein during the post-translational condensation with the phosphatidylinositol-glycan.
Alkaline Phosphatase↗
Human lysosomal acid lipase/cholesteryl ester hydrolase and human gastric lipase: identification of the catalytically active serine, aspartic acid, and histidine residues.
Human lysosomal acid lipase/cholesteryl ester hydrolase (HLAL), human gastric lipase (HGL), and rat lingual lipase (RLL) constitute a family of mammalian lipases characterized by an acidic pH optimum. HGL and RLL are secreted by the chief cells of the stomach and by the serous von Ebner's glands of the tongue, respectively, and hydrolyze dietary longchain triglycerides in the gastrointestinal tract. HLAL, in contrast, catalyzes the intralysosomal degradation of both triglycerides and cholesteryl esters in virtually all cells except erythrocytes. All three enzymes are proposed to be serine esterases with a catalytic Ser-Asp-His triad similar to other lipases, despite their sensitivity towards sulfhydryl modifying reagents. To investigate the role of conserved serine, aspartic acid, and histidine residues in HLAL and HGL, we constructed 24 mutant lipases with single amino acid substitutions using the site-directed mutagenesis approach. Our combined data strongly support the conclusion that Ser153, Asp324, and His355 are components of the catalytic triad of HLAL and HGL. Structural integrity of the conserved His-Gly dipeptide of lipases also appears to be important for neutral lipid hydrolysis, as replacement of His65 by glutamine abolished HLAL and HGL enzymic activity. Substitution of HLAL residues Asp93, Asp130, and Asp328 with glycine, in contrast, had a more pronounced impact on cholesteryl oleate hydrolysis than on triglyceride hydrolysis. These results provide new insights into the structural basis of HLAL and HGL function.
Animals↗
Differential effects of N-methyl-D-aspartic acid and L-homocysteic acid on cerebellar Purkinje neurons.
The effects of N-methyl-D-aspartic acid (NMDA) and L-homocysteic acid (LH) were measured on cerebellar Purkinje neurons. In urethane-anesthetized rats, iontophoretic application of NMDA elicited 3 different effects on the spontaneous activity of Purkinje cells: excitation, inhibition and biphasic responses consisting of excitation followed by inhibition. On the other hand, LH elicited excitation, only, regardless of the actions of NMDA on the same neurons. We also examined the effects of various excitatory amino acid antagonists on NMDA- and LH-mediated responses. Excitatory effects of NMDA were antagonized effectively by D.L-2-amino-5-phosphonovalerate (APV), ketamine, gamma-D-glutamylglycine (DGG), D,L-2-amino-7-phosphonoheptanoate (APH), and were not influenced significantly by L-glutamate diethylester (GDEE). Inhibitory responses of NMDA were antagonized by APV, APH and ketamine. LH-mediated excitations were influenced significantly by DGG and ketamine whereas GDEE, APV and APH failed significantly to attenuate the effects of LH. Based on the differential actions of LH and NMDA and the selectivity of NMDA antagonists for NMDA rather than LH-mediated excitations, it appears that the major actions of LH may not be mediated through NMDA receptor sites, at least in the cerebellum.
2-Amino-5-phosphonovalerate↗
3-Azido-aspartic acid derivatives - orthogonally protected precursors for the stereoselective incorporation of 2,3-diaminosuccinic acid into peptide structures.
The stereoselective synthesis of orthogonally protected 3-azido aspartic acid derivatives is described. The convenience of their application as 2,3-diaminosuccinic acid in peptide chemistry was demonstrated by the incorporation of the nonproteinogenic diamino diacid as a cystine-substitute into the core structure of somatostatin.
Amino Acids, Diamino↗
A patient with pyruvate carboxylase deficiency in the liver: treatment with aspartic acid and thiamine.
A seven-year-old girl with slowly progressive motor neurological impairment and high levels of lactate and pyruvate in blood and cerebrospinal fluid was found to have severe hepatic pyruvate carboxylase deficiency. However, in contrast to other patients with this deficiency, no mental retardation was apparent. Treatment with aspartic acid and thiamine over a period of seven years resulted in biochemical improvement and a stable neurological condition. The level of cognitive functioning remained the same. When treatment with aspartic acid was temporarily discontinued, lactate and pyruvate concentrations increased so markedly that the drug was resumed. This indicates that aspartic acid was the effective drug, and that the effect of thiamine was secondary.
Aspartic Acid↗
Aspartic acid at position 57 of DQ beta chain does not protect against type 1 (insulin-dependent) diabetes mellitus in Japanese subjects.
HLA DQ beta chain, in particular amino acid at position 57, has been reported to contribute to susceptibility and resistance to Type 1 (insulin-dependent) diabetes mellitus in Caucasians. Resistance has been proposed to be conferred by aspartic acid at this position. To ascertain the association of HLA DQ beta and DR beta genes with Type 1 diabetes in Japanese subjects, ten Japanese Type 1 diabetic patients were investigated at DNA level. Genomic DNA was amplified by polymerase chain reaction, and dot blot analysis was carried out using the amplified DNA with allele specific oligonucleotide probes. All patients had aspartic acid at position 57 of at least one of their two DQ beta chains, and there was no significant difference of amino acids at the same position of DR beta chain in patients compared to control subjects. These data indicate that the protective role of aspartic acid at position 57 of DQ beta chain is less significant in Japanese compared with Caucasian subjects.
Aspartic Acid↗
N-acetyl-L-aspartic acid, N-acetyl-alpha-L-aspartyl-L-glutamic acid and beta-citryl-L-glutamic acid in human urine.
N-Acetyl-L-aspartic acid (NA-Asp), N-acetyl-alpha-L-aspartyl-L-glutamic acid (NA-Asp-Glu) and beta-citryl-L-glutamic acid (beta-CG), which are known to occur in the brain, have been isolated from human urine. Their identities were proved by comparing them with synthetic NA-Asp, NA-Asp-Glu and beta-CG using electrophoretic and chromatographic methods and by acid hydrolysis. A method was developed for the quantitation of NA-Asp, NA-Asp-Glu and beta-CG in human urine. It consists of ion-exchange chromatography followed by gas-chromatographic analysis. The amounts of urinary excretion of NA-Asp, NA-Asp-Glu and beta-CG were 41.2 +/- 10.1 (n = 27), 20.8 +/- 9.6 (n = 27) and 30.2 +/- 13.2 (n = 21) mumol/g creatinine in adult males, and 62.2 +/- 16.3 (n = 27), 24.0 +/- 8.2 (n = 27) and 40.5 +/- 21.1 (n = 24) mumol/g creatinine in adult females, respectively.
Adult↗
The catalytic role of the active site aspartic acid in serine proteases.
The role of the aspartic acid residue in the serine protease catalytic triad Asp, His, and Ser has been tested by replacing Asp102 of trypsin with Asn by site-directed mutagenesis. The naturally occurring and mutant enzymes were produced in a heterologous expression system, purified to homogeneity, and characterized. At neutral pH the mutant enzyme activity with an ester substrate and with the Ser195-specific reagent diisopropylfluorophosphate is approximately 10(4) times less than that of the unmodified enzyme. In contrast to the dramatic loss in reactivity of Ser195, the mutant trypsin reacts with the His57-specific reagent, tosyl-L-lysine chloromethylketone, only five times less efficiently than the unmodified enzyme. Thus, the ability of His57 to react with this affinity label is not severely compromised. The catalytic activity of the mutant enzyme increases with increasing pH so that at pH 10.2 the kcat is 6 percent that of trypsin. Kinetic analysis of this novel activity suggests this is due in part to participation of either a titratable base or of hydroxide ion in the catalytic mechanism. By demonstrating the importance of the aspartate residue in catalysis, especially at physiological pH, these experiments provide a rationalization for the evolutionary conservation of the catalytic triad.
Animals↗
D-Aspartic acid: an endogenous amino acid with an important neuroendocrine role.
D-Aspartic acid (d-Asp), an endogenous amino acid present in vertebrates and invertebrates, plays an important role in the neuroendocrine system, as well as in the development of the nervous system. During the embryonic stage of birds and the early postnatal life of mammals, a transient high concentration of d-Asp takes place in the brain and in the retina. d-Asp also acts as a neurotransmitter/neuromodulator. Indeed, this amino acid has been detected in synaptosomes and in synaptic vesicles, where it is released after chemical (K(+) ion, ionomycin) or electric stimuli. Furthermore, d-Asp increases cAMP in neuronal cells and is transported from the synaptic clefts to presynaptic nerve cells through a specific transporter. In the endocrine system, instead, d-Asp is involved in the regulation of hormone synthesis and release. For example, in the rat hypothalamus, it enhances gonadotropin-releasing hormone (GnRH) release and induces oxytocin and vasopressin mRNA synthesis. In the pituitary gland, it stimulates the secretion of the following hormones: prolactin (PRL), luteinizing hormone (LH), and growth hormone (GH) In the testes, it is present in Leydig cells and is involved in testosterone and progesterone release. Thus, a hypothalamus-pituitary-gonads pathway, in which d-Asp is involved, has been formulated. In conclusion, the present work is a summary of previous and current research done on the role of d-Asp in the nervous and endocrine systems of invertebrates and vertebrates, including mammals.
Animals↗
Phase I trial of combination therapy of cancer with N-phosphonacetyl-L-aspartic acid and dipyridamole.
While N-phosphonacetyl-L-aspartic acid (PALA), an inhibitor of de novo pyrimidine biosynthesis, demonstrated a unique spectrum of activity during preclinical drug evaluation, multiple clinical trials have shown it to possess minimal clinical activity. One explanation for the disappointing results is the possibility that tumor cells are able to utilize circulating uridine in the synthesis of pyrimidines (salvage pathway). Dipyridamole, an inhibitor of nucleoside transport, has been demonstrated experimentally to potentiate the cytotoxicity of PALA significantly. In addition, this agent has a long safety record when used clinically in man. A phase I trial of this two-drug combination was therefore conducted, with a fixed oral dose of dipyridamole (50 mg/m2 every 6 h) and an escalating i.v. dose of PALA administered every 3 weeks. The dose-limiting toxicity with this schedule was diarrhea and abdominal cramping pain at a PALA dose of 3900-4200 mg/m2. Among the 65 patients participating in this trial 4 objective responses (2 partial, 2 minimal) were observed. Because of the potential for unique clinical synergy between PALA and dipyridamole further investigation should be considered.
Adult↗
Collateral sensitivity to N-(phosphonacetyl)-L-aspartic acid in a line of P388 leukemia cells selected for resistance to L-(alpha S, 5S)-alpha-amino-3- chloro-4,5-dihydro-5-isoxazoleacetic acid (acivicin).
Administration of N-(phosphonacetyl)-L-aspartic acid (PALA) is ineffective in treating mice bearing the parent P388 leukemia line; however, such treatment becomes highly effective when a cell line, P388/ACIA, derived from P388/0 was selected for resistance to another antimetabolite, acivicin. The observed phenomenon of collateral sensitivity is associated with a significantly higher inhibition of the specific activity of carbamyl phosphate synthetase II, pyrimidine nucleoside kinases, adenine phosphoribosyl transferase, and hypoxanthine phosphoribosyl transferase in the PALA-sensitive line, P388/ACIA. Twenty-four hr following administration of PALA, 200 mg/kg, the 10% lethal dose i.p. to tumor-bearing mice, the intracellular concentrations of uridine triphosphate and cytidine triphosphate were decreased in the P388/ACIA, PALA-sensitive cells, whereas no significant change in the corresponding nucleotide pool sizes was observed in P388/0, PALA-resistant line. Moreover, the purine nucleotide pool demonstrated a significant expansion of adenosine triphosphate and guanosine triphosphate only in the P388/ACIA line following a similar treatment with PALA. It is proposed that the imbalance in the generation of pyrimidine and purine nucleoside triphosphate pools may explain the observed collateral sensitivity to PALA in P388/ACIA leukemia line.
Adenine Phosphoribosyltransferase↗