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PubMed1992

Racemization of aspartic acid in human articular cartilage.

The rate of racemization of aspartic acid was measured in young and aged human femoral head cartilage. Normal femoral heads were obtained at postmortem, osteoarthritic specimens at operations for total hip replacement. In order to distinguish between the aspartic acid racemization in collagen from that in proteoglycan (PG), in addition to native tissue, we tested cartilage specimens from which PG had been enzymatically removed. Preliminary results indicate that there is only a very slow collagen turnover in normal adult cartilage. The same is true of residual cartilage from osteoarthritic femoral heads, indicating no rapid repair except where osteophytes are formed. Native, PG-containing cartilage, whether normal or osteoarthritic was found to have unexpectedly high racemization rates.

Adult↗
PubMed2000

Age-related changes in the D-aspartic acid content of the teeth of the senescence-accelerated mouse.

It is known that D-aspartic acid increases with age in dentine. Here, age-related changes in the D to L-aspartic acid (D/L) ratios of the lower teeth of two different sublines of the senescence-accelerated mouse (SAM), SAMP2/Iw (SAM, prone 2/Iwate) and SAMR1/Iw (SAM, resistant 1/Iwate) were measured by gas chromatography. The D/L ratio of the molars increased with advancing age, whereas that of the incisors did not. In mice younger than 6 months of age the D/L ratio of the molars from SAMP2/Iw tended to be higher than that from SAMR1/Iw, whereas the converse applied to older mice. Racemization in the molars occurred significantly faster in SAMR1/Iw than SAMP2/Iw (p = 0.01-0.001). Analysis according to the kind of tooth showed that the D/L ratio increased gradually in the order incisors < third molars < second molars < first molars, indicating that the ratio was higher the earlier the molars formed. As racemization depends upon the environmental temperature, the rectal temperatures of the mice were also examined. The rectal temperature of SAMP2/Iw was highest when they were 2 months old, but declined rapidly thereafter, whereas the rectal temperature of SAMRI/Iw was highest when they were 6 months old, after which it declined gradually. These results indicate that the D-aspartic acid contents of the molars of SAMR1/Iw and SAMP2/Iw increase with age in a different fashion and suggest that the fashion was determined by the body temperature, but not by the senescence-accelerated age.

Aging↗
PubMed1982

Anti-tumor activity of daunorubicin linked to poly-L-aspartic acid.

Daunorubicin was bound to poly-L-aspartic acid via the methylketone side chain of the drug to avoid reaction of the sugar amino group believed to be essential for optimal drug activity. Attachment of the drug to the polyamino acid by an ester linkage was achieved by nucleophylic substitution reaction of 14-bromo-daunorubicin. Compared with free daunorubicin, the polymeric derivative was less cytotoxic to HeLa cells in vitro, but more effective against all tumor models tested (P388 leukemia, Gross leukemia, MS-2 sarcoma). The binding to the polypeptide markedly reduced drug toxicity but only slightly decreased drug potency. The daunorubicin-poly-L-aspartic acid conjugate demonstrated antitumor activity comparable to that of doxorubicin in leukemia models, but superior to that of doxorubicin in a solid tumor model (MS-2 sarcoma).

Animals↗
PubMed2005

Occurrence of D-aspartic acid in human seminal plasma and spermatozoa: possible role in reproduction.

OBJECTIVE: To determine D-aspartic acid (D-Asp) in human seminal plasma and spermatozoa in fertile and infertile donors. DESIGN: Prospective observation study. SETTING: Department of Pathophysiology for Human Reproduction, Hospital "S. Luca," Salerno, Italy, and Department of Neurobiology and Comparative Physiology, Zoological Station "A. Dohrn," Naples, Italy. PATIENT(S): Ten normospermic, 10 oligoasthenoteratospermic, and 10 azoospermic (nonobstructive) men. INTERVENTION(S): D-aspartic acid was determined by a specific enzymatic high-performance liquid chromatography method on purified seminal plasma and on isolated spermatozoa and by an immunohistochemical method using light and electronic microscopic techniques. MAIN OUTCOME MEASURE(S): Concentration of D-Asp in seminal plasma and in isolated spermatozoa; subcellular localization of D-Asp in the acrosome and nucleus. RESULT(S): The concentration of D-Asp in seminal plasma and in spermatozoa was significantly reduced in oligoasthenoteratospermic donors. In the seminal fluid of normospermic donors, D-Asp occurs at a concentration of 80 +/- 12 nmol/mL semen (10.4 +/- 1.5 microg/mL), whereas 26 +/- 6 nmol/mL semen were found in oligoasthenoteratospermic donors, and 12 +/- 1.5 nmol/mL semen were found in azoospermic donors. In spermatozoa from normospermic donors, D-Asp occurred at a concentration of 130 +/-15 fmol per spermatozoa (17.0 +/- 1.96 ng per spermatozoa), vs. 60.5 +/- 5.0 fmol per spermatozoa from oligoasthenoteratospermic subjects. Other D-amino acids analyzed were not present in seminal plasma or in spermatozoa in a significant concentration compared with D-Asp. CONCLUSION(S): D-aspartic acid occurs in human seminal plasma and spermatozoa and is implicated in male fertility.

Adult↗
PubMed1997

Evaluation of D-amino acid levels in rat by gas chromatography-selected ion monitoring mass spectrometry: no evidence for subacute toxicity of orally fed D-proline and D-aspartic acid.

Sprague-Dawley rats received deionized water (controls) during 28 days or drinking water with added D-proline, L-proline, D-aspartic acid or L-aspartic acid corresponding to a mean daily load of approximately 50 mg amino acid enantiomer kg-1 body weight. Parameters indicating the physiological status (food intake and body weight, glutamic-oxalic-transaminase, glutamic-pyruvic-transaminase, alkaline phosphatase, urea and creatinine in serum, and creatine and osmomolality of urine) were determined. After 28 days the weights of the supposed target organs of toxicity (kidney, liver, brain, thymus) were determined and organs were inspected for macroscopic and microscopic alterations. No pathological changes in the organs were observed and no signs of subacute toxicity (liver, kidney) were found. In serum, homogenates of liver, kidney and brain, and in part, in urine, the amounts of D-amino acids (D-AAs) were quantitatively determined using chiral phase capillary gas chromatography-selected ion monitoring mass spectrometry. Significant levels of certain D-AAs (Ala, Pro, Ser, Asx, Glx, Orn and Lys) were already detectable in kidney and liver homogenates and serum of controls. In brain homogenates the highest amounts among the D-AAs were found for D-Ser (up to 382 nmol g-1), moderate amounts for D-Ala, D-Asx and D-Glx, and, in a few cases, trace amounts for D-Orn and D-Lys (1-2 nmol g-1). D-Pro was not detected either in the brains of controls or in the brains of animals loaded with D-Pro. Feeding with D-Pro resulted in a 20-30 fold increased renal excretion of D-Pro at the end of the experiment. Continuous feeding with D-Asp did not increase renal excretion of this enantiomer, but in the serum, higher amounts (0.8-4.0 mumol-1) were determined in comparison to the control group (0.3-0.9 mumol-1). Feeding with D-Pro led to an increase of this enantiomer in serum (1.3-10.5 mumol-1). Feeding with D-Asp did not increase its amounts in brain homogenates (38 and 43 nmol g-1) in comparison to controls.

Amino Acids↗
PubMed1984

Whole-body distribution of 11C-(4)-L-aspartic acid in rats.

Enzymatic synthesis of 11C-(4)-L-aspartic acid was undertaken using commercially available wheat germ phosphoenolpyruvate carboxylase. Whole-body distribution of the radioactive compound in rats showed higher accumulation in the salivary gland, glandular stomach and the pancreas, as well as in the lungs. Within 60 minutes after intravenous injection of 11C-(4)-L-aspartic acid, about 60% is removed as 11CO2 by expiration, indicating that the carbon atom at the fourth position of the radioactive compound is easily subjected to decarboxylation.

Animals↗
PubMed2002

Age estimation by measuring the racemization of aspartic acid from total amino acid content of several types of bone and rib cartilage: a preliminary account.

Age estimation has been often performed based on the rate of aspartic acid racemization using bones. In this study, we investigated various kinds of bone and a cartilage for suitability to estimate age by racemization. Ten male cadavers aged 22 to 77 years at death were selected, and bone specimens and cartilage were taken from seven sites in each individual. The rate of racemization of aspartic acid among total amino acid contained in each specimen was analyzed by gas chromatography. The correlation coefficient between the rate of racemization and chronological age was relatively high in the sternum, skull, and femur. The rates of aspartic acid racemization were high in the costal cartilage, femur, and skull. In addition, we found that the rate of racemization was only slightly lower after the second irrigation than after the first irrigation in femur and skull bone specimens, but those of others were significantly lower. These findings showed that among the six different bones and rib cartilage, the skull and femur might be used most effectively for age estimation using total amino acid fraction.

Adult↗
PubMed2001

Purification and characterization of poly(aspartic acid) hydrolase from Sphingomonas sp. KT-1.

Poly(aspartic acid) (PAA) hydrolase was purified from Sphingomonas sp. KT-1 (JCM10459). The purified hydrolase degraded thermally synthesized PAA to oligomers. The molecular mass of PAA hydrolase was 30 kDa and the isoelectric point was 8.9. The optimum values of pH and temperature for PAA degradation were 10.0 and 40 degrees C, respectively. The investigation of the effect of inhibitors for the PAA-degrading activities has revealed that the PAA hydrolase is a serine-type hydrolase. The structural analysis of PAA-degraded products using (1)H and (13)C nuclear magnetic resonances has indicated that the purified enzyme hydrolyzes selectively the beta-amide linkage connecting with beta-aspartic acid units in PAA.

Hydrogen-Ion Concentration↗
PubMed1984

Vasopressin release by D-aspartic acid, morphine and prolyl-leucyl-glycinamide (PLG) in DI Brattleboro rats.

The L-asparaginase activities of the brains of the Wistar, heterozygous and homozygous Brattleboro rats divided into three parts namely the anterior, middle and posterior which respectively contained cerebral cortex, hippocampus + midbrain + thalamus + hypothalamus cerebellum + pons + medulla oblongata were estimated. The L-asparaginase activities of all the three parts in the homozygous Brattleboro rats were significantly higher than in the Wistar rats as well as in the heterozygous Brattleboro rats. Twenty min following the injections of 200 mg/kg D-aspartic acid, 20 mg/kg morphine, 200 mg/kg D-aspartic acid + 20 mg/kg morphine, 6 mg/kg prolyl-leucyl-glycinamide (PLG) and 6 mg/kg PLG + 20 mg/kg morphine the L-asparaginase activities of all three parts of the homozygous Brattleboro rat brains were found to be significantly inhibited. After having seen the suppressive effect of the drugs and their combinations used before the homozygous Brattleboro rats were given D-aspartic acid, morphine, D-aspartic acid + morphine, PLG and PLG + morphine for seven days. Then their plasma vasopressin levels were determined by RIA. The treatments applied to the homozygous Brattleboro rats caused the appearance of a significant amount vasopressin in the plasma. The results were interpreted as evidence for the fact that the inhibition of the brain L-asparaginase provides and/or accelerates the biosynthesis and/or release of vasopressin. As morphine has a vasopressin releasing and a brain L-asparaginase inhibiting effect the antidiuretic action of morphine was considered to be linked to its inhibitory effect on the brain L-asparaginase.

Animals↗
PubMed1975

Action of (1-des(aspartic acid), 8-isoleucine) angiotensin II upon the pressor and steroidogenic activity of angiotensin II.

The vascular and steroidogenic responses to (1-Sarcosine, 8-Isoleucine)-, and to (1-Des (Aspartic acid), 8-Isoleucine) angiotensin II were compared in bilaterally nephrectomized, ACTH-suppressed dogs receiving constant infusions of angiotensin II. Aldosterone secretion rate was significantly inhibited by pretreatment with 200 ng/Kg/min of the heptapeptide, (1-Des(Aspartic acid), 8-Isoleucine) ang II, but not by similar doses of the octapeptide, (1-Sarcosine, 8-Isoleucine) ang II. In contrast, the pressor action of ang II was unaffected by (1-Des (Aspartic acid), 8-Isoleucine) ang II though significant inhibition occurred with relatively small doses of (1-Sarcosine, 8-Isoleucine) ang II. This study suggests that: (a) angiotensin receptors in adrenal cortex and vascular smooth muscle are functionally different, and (b) (1-Des(Aspartic acid),8-Isoleucine) angiotensin II is a specific antagonist of steroidogenic effect of ang II.

Adrenal Cortex↗
PubMedDate not supplied

[Effect of psychotropic substances and gamma-aminobutyric acid analogs and derivatives on the release of 3H-D-aspartic acid from perfused synaptosomes of the rat cerebral cortex].

It was shown in experiments in vitro that neuroleptics haloperidol and sulpiride, antidepressants desipramine and amitriptyline, nootropic agent piracetam, benzodiazepine tranquillizer phenazepam, psychostimulant phenamine and agonist of GABA A-receptors tetrahydroisoxazolopyridinol depending on the concentration in the micromolar range decrease K+-stimulated release of 3H-D-aspartic acid from rat brain cortex synaptosomes. Agonists of GABA B-receptors phenibut and baclofen as well as valproate and sodium oxybutyrate failed to exert a noticeable effect on the process under study.

Animals↗
PubMed1985

Release of D-[3H]aspartic acid from the rat striatum. Effect of veratridine-evoked depolarization, fronto-parietal cortex ablation, and striatal lesions with kainic acid.

The spontaneous and depolarization-evoked release of radiolabeled D-aspartic acid, previously taken up by rat striatal slices, was studied by using a superfusion system. Veratridine (10-50 microM), electrical field stimulation (20 Hz, 1.0 V, 60 sec), and potassium (53 mM) markedly potentiated the release of D-[3H]aspartate from striatal slices. The release of L-[3H]glutamate was also increased by veratridine, according to a pattern and time course of release similar to that of D-[3H]aspartate. However, the ratio of D-[3H]aspartic acid release evoked by veratridine over spontaneous levels of release was much higher when compared to that of radiolabeled L-glutamate. Omission of calcium from the superfusion medium almost completely suppressed D-[3H]aspartate release evoked by veratridine or by electrical stimulation whereas high K+-evoked release of the [3H]amino acid was only slightly reduced. However, increasing Mg2+ concentration to 12 mM in the superfusion medium did substantially block D-[3H]aspartate release induced by K+-depolarization. Additional experiments showed that tetrodotoxin (1 microM), a blocker of voltage-dependent Na+ channels, totally abolished veratridine-evoked release of D-[3H]aspartate from striatal slices. Finally, lesion studies showed that unilateral ablation of the frontoparietal cortex was accompanied by a significant decrease in the high-affinity uptake of striatal D-[3H]aspartate and by a large and parallel loss from striatal slices in D-[3H]aspartate release evoked by either veratridine or high K+. In contrast, unilateral injection of kainic acid into the striatum did not influence depolarization-evoked release of D-[3H]aspartate from striatal slices. The findings reported suggest that D-[3H]aspartic acid may be taken up preferentially and then released, in a Ca2+-dependent manner, by veratridine and electrical stimulation from nerve terminals belonging to the cortico-striatal pathway. In addition, the results provide further support for the view that excitatory amino acids may act as neurotransmitters at the cortico-striatal nerve fibers.

Animals↗
PubMed1991

Substitution of aspartic acid-686 by histidine or asparagine in the human androgen receptor leads to a functionally inactive protein with altered hormone-binding characteristics.

We have identified two different single nucleotide alterations in codon 686 (GAC; aspartic acid) in exon 4 of the human androgen receptor gene in three unrelated families with the complete form of androgen insensitivity. One mutation (G----C) results in an aspartic acid----histidine substitution (with 15-20% of wild-type androgen-binding capacity), whereas the other mutation (G----A) leads to an aspartic acid----asparagine substitution (with normal androgen-binding capacity, but a rapidly dissociating ligand-receptor complex). The mutations eliminate a Hinfl restriction site. Screening for the loss of the Hinfl site in both families with the Asp----Asn mutation resulted in the recognition of heterozygous carriers in successive generations of each. Both mutant androgen receptors were generated in vitro and transiently expressed in COS and HeLa cells. The receptor proteins produced had the same altered binding characteristics as those measured in fibroblasts from the affected subjects. R1881-activated transcription of a GRE-tk-CAT reporter gene construct was strongly diminished by both mutant receptors and was only partially restored using a 100-fold higher concentration of ligand compared with wild-type receptor. Thus, aspartic acid-686 appears essential for normal androgen receptor function. Substitution of this amino acid residue, by either histidine or asparagine, results in androgen insensitivity and lack of androgen-dependent male sexual differentiation.

Adult↗
PubMed2006

Effects of amino acid substitutions in and around the arginine-glycine-aspartic acid (RGD) sequence on fertilization and parthenogenetic development in mature bovine oocytes.

Integrins have been shown to be involved in the process of fertilization and many integrin-ligand interactions are mediated through the recognition of an arginine-glycine-aspartic acid (RGD) sequence. Despite the fact the RGD domain is a principal player in determining the functional characteristics of an adhesive protein, increasing evidence has accumulated implicating the amino acids flanking the RGD sequence in determining the functional properties of the RGD-containing protein. A set of linear peptides in which the amino acid sequence in and around the RGD tri-peptide was modified was synthesized to better understand the specificity of the RGD-receptor interaction. Mature oocytes were fertilized in vitro in the presence of RGD-containing and RGD-modified peptides. Both the RGD-containing and RGD-modified peptides impaired the ability of sperm to fertilize bovine oocytes, illustrated by a reduction in cleavage. The linear modified RGD containing peptides were also examined for their ability to induce parthenogenetic development with the objective of providing a linear RGD peptide with greater biological activity than the one (GRGDSPK) used previously (Campbell et al., 2000). The data demonstrate the specificity of the receptor for the RGD sequence, further implicate the involvement of integrins in the process of bovine fertilization, and illustrate the importance of the amino acids surrounding the RGD sequence in determining the binding and functional properties of RGD-containing peptides. The data support the findings that a linear RGD peptide can block fertilization and that amino acids around the RGD sequence have an impact on the biological activity of the receptor.

Amino Acid Substitution↗
PubMed1988

Reversible receptor methylation is essential for normal chemotaxis of Escherichia coli in gradients of aspartic acid.

The chemotaxis of wild-type cells of Escherichia coli and double mutants lacking the methyltransferase and the methylesterase activities of the receptor modification system has been compared in spatial gradients of aspartic acid. Previous studies showing that a chemotactic response can be observed for the mutant raised questions about the role of methylation in the bacterial memory. To clarify the role of methylation, the redistribution of bacteria in stabilized defined gradients of aspartic acid was monitored by light scattering. There was no redistribution of the mutant cells in nonsaturating gradients of aspartic acid, but over the same range these mutant bacteria were observed to respond and to adapt during tethering experiments. In large saturating gradients of aspartate, slight movement of the mutant up the gradient was observed. These results show that dynamic receptor methylation is required for the chemotactic response to gentle gradients of aspartic acid and that methylation resets to zero and is part of the normal wild-type memory. There are certain gradients, however, in which the methylation-deficient mutants show chemotactic ability, thus explaining the apparent anomaly.

Aspartic Acid↗
PubMed1986

Comparison of the suppressive effects of L-aspartic acid and chlorpromazine + diazepam treatments on opiate abstinence syndrome signs in men.

According to the hypothesis implying that the main reason of physical dependence on opiate is the inhibition of brain L-asparaginase activity and L-aspartic acid gradually decreases compulsory opiate intake so that physical dependence disappears by itself, 31 opiate addicts were given 8 g L-aspartic acid for 7 days after withdrawal from opiate and appearance of abstinence syndrome signs. The attenuations by L-aspartic acid of the abstinence syndrome signs were statistically compared with those obtained from other 12 opiate addicts received daily 50 mg chlorpromazine + 60 mg diazepam which have long been used to suppress abstinence syndrome because of their multiple receptor blocking and sedative effects. The intensity and duration of 13 signs out of 16 ones were found to be significantly more alleviated and shortened in the addicts treated with L-aspartic acid.

Aspartic Acid↗
PubMed2000

[Estimation of age from teeth using the racemization of aspartic acid (racemization method)].

We report a method for estimation of age from teeth using the racemization of amino acids (racemization method). This method is based on the characteristics of the constant age-related increase in the amount of D-aspartic acid in dentin. We estimated age by measuring the ratio of D-aspartic acid to L-aspartic acid, i.e. the ratio of racemization ¿ratio of D/L, ln[(1 + D/L)/(1 - D/L)]¿. Because different D/L ratios have been obtained from different teeth in the same individuals and from different sites of dentin in the same tooth, we usually prepare bucco-lingual longitudinal sections at the central part of each tooth, and prepare samples of powdered whole dentin. This powder is then mixed and used to measure the D/L ratio in the dentin. To accurately estimate age from forensic specimens, we simultaneously measured the D/L ratios in more than four control teeth of the same type obtained from subjects of known age. Use of control teeth is necessary because it is sometimes difficult to maintain constant running conditions for gas chromatography to obtain reproducible values in different runs. Therefore, for every measurement, we determined an equation for calculating age from the D/L ratios of control teeth, and estimated the age of the specimen tooth by substituting in its D/L ratio. The most reliable results were obtained using samples of lower incisors or premolars, which are single-rooted teeth with a relatively small volume of dentin. Thus sampling of the dentin is easier than for other teeth. It is better to keep control teeth desiccated because racemization does not proceed readily under such conditions. The deviation from the actual age in the cases we examined was less than 3 years. Thus, racemization of amino acids can be used for accurate estimation of age from teeth.

Adolescent↗