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At least 217 records · Page 12Linked to original sources
PubMed1999

Hepatobiliary transport of bile acid amino acid, bile acid peptide, and bile acid oligonucleotide conjugates in rats.

Uptake of drugs by bile acid carriers could account for the selectivity of drug actions in the gut and liver. We have previously shown that conjugation of xenobiotics with bile acids facilitates their transfer to hepatocytes and ileal enterocytes. In this study L-alanine and 2 biooligomers, the tetrapeptide L-(ala)(4) and a 15 mer oligodeoxynucleotide (ODN) were coupled covalently via linker molecules to the 3-position of bile acids. The L-alanine-coupled bile acid conjugates were rapidly taken up by the liver and efficiently eliminated into bile. These compounds mimicked hepatic transport of bile acids. Also in case of the tetrapeptide (ala)(4), bile acid conjugation significantly improved hepatic and intestinal cell uptake and rendered the peptide conjugate resistant to peptidases. Because uptake by isolated hepatocytes was not dependent on sodium ions and was blocked by ochratoxin A, we assume basolateral transport by an oatp-type bile acid carrier. In the case of the 15 mer ODN, normal and bile acid-conjugated oligodeoxynucleotide appeared intact in bile but without marked improvement of hepatocellular uptake and biliary elimination. We conclude that bile acids can deliver small peptides to gut and parenchymal liver cells via bile acid transport pathways, whereas in the case of oligonucleotides an attached bile acid was not sufficient to shuttle them successfully into hepatocytes.

Alanine↗
PubMed1995

Electrostatic effects of surface acidic amino acid residues on the oxidation-reduction potentials of the flavodoxin from Desulfovibrio vulgaris (Hildenborough).

The flavodoxin from Desulfovibrio vulgaris (Hildenborough) is a member of a family of small, acidic proteins that contain a single noncovalently bound flavin mononucleotide (FMN) cofactor. These proteins function as low-potential one-electron transferases in bacteria. A distinguishing feature of these flavoproteins is the dramatic decrease in the midpoint potential of the semiquinone/hydroquinone couple of the FMN upon binding to the apoprotein (-172 mV for FMN free in solution versus -443 mV when bound), a perturbation thought to be essential for physiological function. The structural basis of this phenomenon is not yet thoroughly understood. In this study, the contribution of six acidic residues (Asp62, Asp63, Glu66, Asp95, Glu99, and Asp106) to the perturbation of the redox properties of the cofactor has been investigated. These residues are clustered about the FMN binding site within 13 A of the N(1) atom of the cofactor. Using oligonucleotide-directed mutagenesis, these residues were neutralized in various combinations through the substitution of asparagine for aspartate and glutamine for glutamate. Seventeen mutant flavodoxins were generated in which one to all six acidic residues were systematically neutralized, often in various spatial configurations. There was no obvious correlation between the midpoint potentials for the oxidized/semiquinone couple and general electrostatic environment, although some differences were noted. However, the midpoint potential for the semiquinone/hydroquinone couple for each of the mutants was less negative than that of the wild type. These increases are strongly correlated with the number of acid to amide substitutions, with an average contribution of about 15 mV per substitution. Collectively, the unfavorable electrostatic environment provided by these acidic residues accounts for approximately one-third of the large midpoint potential shift for the semiquinone/hydroquinone couple that typifies the flavodoxin family, apparently through the destabilization of the flavin hydroquinone anion.

Amino Acids, Dicarboxylic↗
PubMed1968

Excitatory acidic amino acids and the cation content and sodium ion flux of isolated tissues from the brain.

1. Sample from the neocortex and piriform cortex of guinea pigs and rats were incubated in inulin-containing glucose-saline. Their intracellular (non-inulin) space contained 19-27muequiv. of Na(+)/g. of original tissue. These values were stable between 30 and 100min. after incubation commenced, but addition of (22)NaCl to the neocortical samples showed them to be associated with a flux of 400muequiv. of Na(+)/g. of tissue/hr. 2. Addition of 0.5-10mm-l-glutamic acid or 0.1mm-N-methyl-dl-aspartic acid rapidly increased the tissue's Na(+) content; N-acetyl-dl-aspartic acid was without action. 3. During the first 1-1.5min. after the addition of l-glutamic acid to neocortical samples their Na(+) content increased at 600muequiv./g. of tissue/hr., and the rate of (22)Na(+) influx corresponded to 1230muequiv. of Na(+)/g./hr. These rates were calculated to be sufficiently rapid to account for loss of the tissue's normal membrane potential within 1-2sec. of the addition of the acid. 4. In addition, a rapid but more limited loss of K(+) took place after the addition of l-glutamic acid or the methylaspartic acid; on continued incubation tissue K(+) content increased, as also did the intracellular volume of the tissue, from its original 670mul./g. to 1100mul./g. 5. Interpretation of these and of associated changes is offered in terms that involve a cation pump and the permeability changes associated with the nerve impulse.

Amino Acids↗
PubMed1988

Purification and characterization of an acidic amino acid specific endopeptidase of Streptomyces griseus obtained from a commercial preparation (Pronase).

A protease was purified 163-fold from Pronase, a commercial product from culture filtrate of Streptomyces griseus, by a series of column chromatographies on CM-Toyopearl (Fractogel), Sephadex G-50, hydroxyapatite, and Z-Gly-D-Phe-AH-Sepharose 4B using Boc-Ala-Ala-Pro-Glu-pNA as a substrate. The final preparation was homogeneous by polyacrylamide gel electrophoresis (PAGE), sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), and gel isoelectric focusing. Studies on the substrate specificity with peptide p-nitroanilides revealed that this protease preferentially hydrolyzed peptide bonds on the carbonyl-terminal side of either glutamic acid or aspartic acid. It was most active at pH 8.8 for the hydrolysis of Boc-Ala-Ala-Pro-Glu-pNA. The molecular weight of the protease was estimated to be 20,000 by gel filtration on Sepharose 6B using 6 M guanidine hydrochloride as an eluent, and 22,000 by SDS-PAGE in the presence of 2-mercaptoethanol. The isoelectric point of the enzyme was 8.4. The enzyme was inactivated by diisopropyl phosphofluoridate (DFP) but not by p-chloromercuribenzoate (PCMB) or EDTA.

Amino Acids↗
PubMed1980

Actions of glutamate, kainate, dihydrokainate and analogues on leech neurone acidic amino acid receptors.

Intracellular recordings have been made from leech Retzius cells. L-Glutamate and kainate both excite these cells, kainate being about 100 times more potent than glutamate. Cross desensitization was observed between glutamate and kainate. Dihydrokainate was found to be equipotent with kainate on these neurones. Esterification of either kainate or dihydrokainate rendered the compounds inactive as did the addition of a benzyloxycarbonyl group on the nitrogen of both compounds. These results suggest that the double bond in the side chain of kainate is not necessary for its potent activity on leech Retzius neurones. But, that free carboxyl groups and an unsubstituted nitrogen are essential for glutamate-like activity.

Amino Acids↗
PubMed1996

Isolation and characterization of mutants of Arabidopsis thaliana with increased resistance to growth inhibition by indoleacetic acid-amino acid conjugates.

Two mutants of Arabidopsis thaliana that are resistant to growth inhibition by indole-3-acetic acid (IAA)-phenylalanine have been isolated. Both mutants were 2- to 3-fold more resistant than wild type to inhibition by IAA-phenylalanine, IAA-alanine, and IAA-glycine in root growth assays. The mutant icr1 (but not icr2) also shows some resistance to IAA-aspartate. Studies using 3H-labeled IAA-phenylalanine showed that the uptake of conjugate from the medium by icr1 was the same as wild type and was reduced by about 25% in icr2. No differences in hydrolysis of the exogenous conjugate were detected between the mutants and their wild-type parents. There was no significant metabolism of the IAA released from the [3H]IAA-phenylalanine, whereas exogenous [3H]IAA was rapidly metabolized to two unidentified products considerably more polar than IAA. Analysis of a cross between icr1 and icr2 indicated that these mutations were at distinct loci and that their effects were additive, and preliminary mapping data indicated that icr1 and icr2 were located at the top and bottom of chromosome V, respectively.

Amino Acids↗
PubMed1988

Rheogenic transport of basic and acidic amino acids across the brush border of Necturus small intestine.

In studies with isolated Necturus intestine, glutamate (Glu-) and Na+ each enhanced the mucosal influx of the other. Measurement of apical membrane potential, Va, with microelectrodes revealed a rapid depolarization with addition of 10 mM mucosal Glu-. This depolarization was Na+ dependent. Upon complete removal of Cl- from the bathing medium Va hyperpolarized and the Glu- -induced depolarization increased significantly. However, removal of Cl- did not alter the total Glu- influx. These data suggest that external Cl- attenuates the rheogenicity of Na+/Glu- cotransport in the apical membrane of the absorptive cells. We have presented a model consistent with these observations in which Cl- competes with one -COO- group of Glu- for its binding site on the carrier. The two complexes which may form, carrier/Glu-/2Na+ or carrier/Glu-/2Na+/Cl-, allow for either electrogenic or electroneutral transport of Glu-, depending on the ratio [Glu-]/[Cl-] in the extracellular fluid. In other experiments, addition of mucosal L-lysine (Lys+) induced a rapid depolarization of Va. In the presence of Na+, the depolarization appeared to be saturable with respect to Lys+ concentration. In Na+-free media, however, the depolarization increased with Lys+ concentration up to a maximum at 10 mM and then decreased to near zero at 30 mM. These data are consistent with a model for Lys+ entry in which an anionic site of the carrier can bind either Na+ or the epsilon-NH3+ group of Lys+. In this model transport of either complex, carrier-/Lys+ or carrier-/Lys+/Na+ (and return of the carrier to the extracellular surface) is rheogenic. However, at higher Lys+ concentrations, the epsilon-NH3+ group of a second Lys+ molecule may bind to the carrier forming a complex, carrier-/2Lys+, which is not transported.

Amino Acids↗
PubMed2001

Colon-specific prodrugs of 5-aminosalicylic acid: synthesis and in vitro/in vivo properties of acidic amino acid derivatives of 5-aminosalicylic acid.

5-aminosalicyl-L-aspartic acid (5-ASA-Asp) and 5-aminosalicyl-L-glutamic acid (5-ASA-Glu) were synthesized and their properties as colon-specific prodrugs of 5-aminosalicylic acid (5-ASA) were investigated employing rats as test animals. Incubation of 5-ASA-Asp and 5-ASA-Glu with the homogenates of tissue and contents of stomach or small intestine released no 5-ASA, indicating that they were stable in this condition. Incubation of 5-ASA-Asp with the cecal contents released 5-ASA 37%, whereas 5-ASA-Glu released only 8% of the dose in 16 h. Plasma concentration of 5-ASA-Asp after intravenous administration decreased rapidly and became undetectable in 60 min. No 5-ASA was detected in the blood, which indicated 5-ASA-Asp was stable in the plasma. After oral administration of 5-ASA-Asp, concentration of 5-ASA, its metabolite N-acetyl-5-ASA, and 5-ASA-Asp in the plasma, feces, and urine was determined. In the plasma, 5-ASA-Asp was not detected and the concentration of 5-ASA or N-acetyl-5-ASA was very low. About 33% of the administered dose was recovered as 5-ASA and N-acetyl-5-ASA and 43% as 5-ASA-Asp from feces, and 20% as 5-ASA and N-acetyl-5-ASA and 1% as 5-ASA-Asp from urine in 24 h. These results suggested that most of 5-ASA-Asp was delivered to the large intestine and about half of the administered dose was activated to liberate 5-ASA. After oral administration of free 5-ASA, fecal recovery was only 7% of the dose in 24 h and more than 80% was recovered from urine. Comparing 5-ASA-Asp and free 5-ASA, the amount of 5-ASA available in the large intestine was much larger, while the amount of 5-ASA in urine, which might be related to the systemic toxicity of 5-ASA, was much lower by the administration of 5-ASA-Asp than free 5-ASA.

Administration, Oral↗
PubMed1992

Acidic amino acids evoke a smaller [Ca2+]i rise in GABAergic than non-GABAergic hippocampal neurons.

Changes in intracellular calcium concentration ([Ca2+]i) in response to topical application of the glutamate agonists N-methyl-D-aspartate (NMDA), or amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) were measured in cultured rat hippocampal neurons loaded with Fluo-3 and visualized in a confocal laser scanning microscope. These neurons were subsequently stained for the presence of the enzyme marker for gamma-amino butyric acid (GABA), glutamate decarboxylase (GAD). GAD-positive, putative interneurons were less responsive to NMDA and AMPA than GAD-negative neurons. The time course of the rise and decay of [Ca2+]i was similar in the two groups of neurons. Also, there was no clear difference in the shape and size of these two neuron groups indicating that the difference between them is not due to diffusion distances. These data indicate that interneurons are probably more able to handle a calcium load than other neurons, a difference that may underly their resistance to treatments which cause degeneration of other neurons in the hippocampus.

Animals↗
PubMed1983

Effects of acidic amino acid antagonists on paired-pulse potentiation at the lateral perforant path.

The glutamate analogue 2-amino-4-phosphonobutyric acid (APB) has been shown to selectively reduce synaptic transmission along the lateral portion of the perforant path input to the dentate gyrus. APB is studied here with respect to effects on paired-pulse potentiation (PPP) along the perforant path. Application of APB causes a reduction in lateral perforant path responses, but also an increase in the %PPP of that response. The effect does not result simply from reducing response size, because the amount of potentiation of matched first responses increases, and also because APB reduces the potentiated response proportionately less than a comparable first response. A similar effect is seen by decreasing extracellular calcium. Reducing lateral perforant path responses with kynurenic acid, which apparently acts on postsynaptic sites, does not have a similar effect on PPP. These results may indicate a presynaptic action of APB, possibly mediated via an effect on presynaptic calcium availability.

Aminobutyrates↗
PubMed1984

Sodium ions regulate a specific population of acidic amino acid receptors in synaptic membranes.

The regulatory effects of Na+ on C1-/Ca2+-dependent and C1-/Ca2+-independent L-glutamate binding sites were examined. In Tris-C1-/Ca2+ buffer, the binding of L-[3H]-glutamate to rat brain synaptic membranes was 5-fold higher than in Tris-acetate buffer. Low concentrations of Na+ (less than 5 mM) markedly depressed L-glutamate binding when assayed in Tris-C1/Ca2+ buffer, and this effect was attenuated by the selective blocker of C1-/Ca2+-dependent binding sites, DL-2-amino-4-phosphonobutyrate (APB). Scatchard analyses indicated that the effect of Na+ was due to a decrease in the number of C1-/Ca2+-dependent binding sites with no change in affinity. In Tris-acetate buffer, low concentrations of Na+ had little effect on L-glutamate binding. Dose-response curves for the inhibition of L-glutamate binding by DL-APB indicated a predominant high-affinity (Ki 5-10 microM) inhibitory component in Tris-C1-/Ca2+ buffer, but mainly a low-affinity component (Ki 1-2 mM) in Tris-acetate buffer and in Tris-C1-/Ca2+ buffer containing Na+. These data indicate that low concentrations of Na+ regulate specifically the C1-/Ca2+-dependent, APB-sensitive class of L-glutamate binding sites.

Aminobutyrates↗