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PubMed1985

The effect of amino acids and dipeptides on sodium-ion transport in rat enterocytes.

Sodium efflux from isolated intestinal epithelial cells was measured during incubation with several different free amino acids and dipeptides. L-Leucine, which is cotransported with sodium across the brush border membrane, significantly stimulated the total sodium efflux and almost all of this increase involved the ouabain-sensitive flux, i.e., the active component. In contrast, glycyl-L-leucine had little or no effect on active sodium efflux either in the presence or absence of 0.1 mM bestatin, a peptide hydrolase inhibitor. A second dipeptide L-carnosine (beta-alanyl-L-histidine) which is poorly hydrolysed by enterocytes also had no effect upon sodium efflux. However, glycylglycine, which has been shown to be cotransported with sodium, did stimulate the ionic efflux. In addition, measurement of sodium uptake by sheets of small intestine showed that glycyl-L-leucine, carnosine and glycyl-L-proline failed to increase the uptake of the ion, while glycylglycine did significantly stimulate sodium uptake. These data indicate that some dipeptides are not cotransported with sodium, while others are. This suggests that there may well be multiple peptide transporters with very different characteristics in the brush border membrane of enterocytes.

Amino Acids↗
PubMed1988

Characterization of the transport system for beta-lactam antibiotics and dipeptides in rat renal brush-border membrane vesicles by photoaffinity labeling.

The uptake of the alpha-aminocephalosporin cephalexin into brush-border membrane vesicles from rat renal cortex was independent on an inward H+-gradient in contrast to the intestinal transport system. The transport system could be irreversibly inhibited by photoaffinity labeling. Two binding polypeptides for beta-lactam antibiotics and dipeptides with apparent molecular weights 130,000 and 95,000 were identified by photoaffinity labeling with [3H]benzylpenicillin and N-(4-azido[3,5-3H]benzoyl) derivatives of cephalexin and glycyl-L-proline. The uptake of cephalexin and the labeling of the respective binding proteins was inhibited by beta-lactam antibiotics and dipeptides as with intestinal brush-border membranes. These data indicate that the transport systems for beta-lactam antibiotics and dipeptides in the brush-border membrane from rat kidney and small intestine are similar but not identical.

Affinity Labels↗
PubMed1990

Uptake of the cephalosporin, cephalexin, by a dipeptide transport carrier in the human intestinal cell line, Caco-2.

The transport of the orally absorbed cephalosporin, cephalexin, was examined in the human epithelial cell line, Caco-2 that possesses intestinal enterocyte-like properties when cultured. In sodium-free buffer, the cells accumulated 1 mM D-[9-14C]cephalexin against a concentration gradient and obtained a distribution ratio of 3.5 within 180 min. Drug uptake was maximal when the extracellular pH was 6.0. Uptake was reduced by metabolic inhibitors and by protonophores indicating that uptake was energy- and proton-dependent. Kinetic analysis of the concentration dependence of the rate of cephalexin uptake showed that a non-saturable component (Kd of 0.18 +/- 0.01 nmol/min per mg protein per mM) and a transport system with a Km of 7.5 +/- 2.8 mM and a Vmax of 6.5 +/- 0.9 nmol/min per mg protein were responsible for drug uptake. Uptake was competitively inhibited by dipeptides. The transport carrier exhibited stereospecificity for the L-isomer of cephalexin. Drug uptake was not affected by the presence of amino acids, organic anions, 4-acetamido-4'-isothiocyanostilbene-2,2'-disulfonic acid or 4,4'-diisothiocyano-2,2'-disulfonic stilbene. Therefore, Caco-2 cells take up cephalexin by a proton-dependent dipeptide transport carrier that closely resembles the transporter present in the intestine. Caco-2 cells represent a cellular model for future studies of the dipeptide transporter.

2,4-Dinitrophenol↗
PubMed1993

H(+)-coupled dipeptide (glycylsarcosine) transport across apical and basal borders of human intestinal Caco-2 cell monolayers display distinctive characteristics.

Transepithelial transport and intracellular accumulation of the dipeptide glycylsarcosine (Gly-Sar) were studied using intact monolayers of the human intestinal epithelial cell line, Caco-2. Gly-Sar transport was demonstrated in both absorptive (apical-to-basal) and secretory (basal-to-apical) directions. In both directions, transport and accumulation were enhanced in the presence of a pH gradient (pHo < pHi). Under conditions similar to those found at the intestinal membrane in vivo (apical pH 6.0, basolateral pH 7.4), net absorption (145.2 pmol/cm2 per h) was observed, although experimental conditions could also be manipulated (apical pH 7.4, basolateral pH 6.0) so that net secretion was observed. Transport and accumulation (in both directions) were inhibited in the presence of either 20 mM (unlabelled) Gly-Sar or 20 mM cephalexin (an aminocephalosporin antibiotic). When added to either the apical or basolateral surface of BCECF (2',7',-bis(2-carboxyethyl)-5(6)-carboxyfluorescein)-loaded Caco-2 cell monolayers Gly-Sar (20 mM), at pH 6.0, caused a marked intracellular acidification, demonstrating that dipeptide absorption is accompanied by H(+)-flow into the cells. Cephalexin (20 mM) had similar effects (as Gly-Sar) when presented at the apical surface but also caused a marked intracellular acidification when perfused into the basolateral chamber at pH 7.4. In contrast, addition of Gly-Sar (20 mM) to the basolateral chamber (at pH 7.4) had no effect. Transepithelial absorption of dipeptides (Gly-Sar) and beta-lactam antibiotics (cephalexin) at low concentrations is predominately via a transcellular route mediated by carrier mechanisms located at both apical and basolateral membranes. Interestingly, Gly-Sar and cephalexin transport across the basolateral membrane (and, therefore, exit from the cell) display both common and distinct characteristics suggesting that more than one mechanism may be responsible for exit into the basolateral space.

Biological Transport↗
PubMed1986

H+ gradient-dependent transport of aminocephalosporins in rat intestinal brush-border membrane vesicles. Role of dipeptide transport system.

The transport of cephalosporin antibiotics in brush-border membrane vesicles isolated from rat small intestine has been studied by a rapid filtration technique, demonstrating a carrier-mediated transport system for aminocephalosporins such as cephradine. In agreement with the transport mechanisms of dipeptides, the uptake of cephradine by brush-border membrane vesicles was Na+-independent and was stimulated in the presence of an inward H+ gradient ([H+]o greater than [H+]i). Cephradine uptake in the presence of an inward H+ gradient was a saturable process with an apparent Km of 9.4 mM, and was markedly inhibited by dipeptides but not inhibited by amino acids. The present data suggest that aminocephalosporins can be transported by a common carrier-mediated system with dipeptides in the intestinal brush-border membranes and this process may be driven by an H+ gradient.

Amines↗
PubMed1993

Expression of human intestinal dipeptide transporter in Xenopus laevis oocytes.

The human colon adenocarcinoma cell line Caco-2 retains the H+/dipeptide cotransporter. To identify the structure of the human dipeptide transporter, we have examined the expression of the transporter in Xenopus laevis oocytes injected with Caco-2 poly(A)+RNA, by monitoring the uptake of bestatin, a dipeptide-like anticancer agent. The bestatin uptake in the poly(A)+RNA-injected oocytes was inhibited by excess glycyl-L-leucine, and showed pH dependence (optimal pH of 5.5-6.0). These observations suggest that the human intestinal dipeptide transporter can be expressed functionally in Xenopus oocytes.

Animals↗
PubMed1993

The in vivo metabolic stability of dipeptide analogues of the quinazoline antifolate, ICI 198583, in mice.

In the search for quinazoline thymidylate synthase inhibitors that are not subject to intracellular polyglutamation, a class of dipeptide analogues of the diglutamate of 2-desamino-2-methyl-N10-propargyl-5,8-dideazafolic acid (ICI 198583-gamma-L-glu) has been evaluated for their stability to in vivo hydrolysis. Replacement of the second glutamate with another amino acid, e.g. alanine, prevented polyglutamation in vitro but such compounds were subject to hydrolysis when injected into mice. The extent of hydrolysis was measured in plasma, liver and kidney by HPLC analysis of tissue removed from mice 1 hr after i.p. injection. The enzyme responsible for this hydrolysis is thought to be a gamma-glutamyl hydrolase which hydrolyses the amide bond, releasing ICI 198583 which may then be polyglutamated. Development of stable dipeptide compounds was achieved by structural modification in two principal ways: either by replacement of the second amino acid (e.g. glutamate or alanine) with its D-enantiomer or removal of the carboxyl on the alpha-carbon of the second amino acid (alpha'-COOH). In this second approach two series of compounds were investigated. Monocarboxylate-derived dipeptides, e.g. ICI 198583-gamma-L-phenylalanine or ICI 198583-gamma-phenylglycine, resulted in stable compounds after removal of the alpha'-COOH (to give -ethylamide and -benzylamide derivatives, respectively). However, for the dicarboxylic amino acids a less clear picture emerged. Although removal of the alpha'-COOH from ICI198583-gamma-L-glutamate to give ICI 198583-gamma-gamma-aminobutyric acid resulted in a stable compound, the corresponding aspartate analogue (-beta-alanine) was subject to hydrolysis.

Animals↗
PubMed1983

Blood-brain barrier permeability to dipeptides and their constituent amino acids.

The penetration of two [14C]-labelled dipeptides, glycyl-L-phenylalanine and glycyl-L-leucine, and of their constituent amino acids into the brain of the rat was measured employing an intracarotid injection technique. The brain-uptakes of the dipeptides were about equal to that of sucrose suggesting a negligible extraction from the blood during the 15-s period of exposure to the peptides. Brain uptakes for L-phenylalanine and L-leucine were large and in agreement with earlier work on these amino acids; self-inhibition by unlabelled amino acids was marked as also inhibition by the typical L-transport system substrate, 2-aminobicyclo (2, 2, 1) heptane-2 carboxylic acid (BCH), whilst the substrate for the A-system, N-methyl-L-aminoisobutyric acid (MeAIB) was without effect. Uptake of L-phenylalanine and L-leucine was not inhibited by dipeptides in 10 mM concentration. The uptakes of [14C]-labelled MeAIB and glycine were not significantly different from that of sucrose. It is concluded that peptide formation effectively excludes the rapidly penetrating L-system amino acids, L-leucine and L-phenylalanine, from access to the L-system channel.

Amino Acids↗
PubMed1991

Excitatory action of some aspartate- and glutamate-containing dipeptides after intracerebroventricular injection in mice.

The effects of some dipeptides, analogues of N-acetyl-alpha-L-aspartyl-L-glutamate, were studied after i.c.v. administration into mice in acute experiments. N-Acetyl-alpha-L-aspartyl-L-glutamate itself did not induce seizures in animals, but prevented glutamate-induced convulsions. All other dipeptides possessed excitatory glutamate-like actions. Some structural requirements for the excitatory effects of the dipeptides are discussed.

Animals↗
PubMed1994

Glutamine dipeptide-supplemented parenteral nutrition maintains intestinal function in the critically ill.

BACKGROUND/AIMS: Long-term total parenteral nutrition is accompanied with mucosal atrophy and subsequent malabsorption syndrome. Current information attests the important role of glutamine in maintaining intestinal structure and function. The aim of this study was to investigate the effect of glutamine dipeptide supplementation on small intestinal absorption capacity during critical illness. METHODS: Twelve intensive care unit patients were uniformly randomized to receive isonitrogenous (0.26 g nitrogen.kg-1.day-1) and isoenergetic (155 kJ.kg-1.day-1) parenteral nutrition over 9 days. The control group received a conventional amino acid solution (1.5 g amino acids.kg-1.day-1), and the test group received a complete amino acid solution containing the dipeptide L-alanyl-L-glutamine (20 g/L). On days 8 and 9, a modified D-xylose test was performed. RESULTS: Excretion of D-xylose during the 5-hour test period was 7.4 +/- 1.1 g (test) vs. 3.8 +/- 0.9 g (control) (P < 0.05). The 2-hour serum D-xylose concentration was 38.7 +/- 3.0 (test) vs. 27.8 +/- 2.9 mg/100 mL (control) (P < 0.05). Kinetic evaluation showed higher maximum D-xylose blood concentration and higher values for the area under the curve with the peptide. CONCLUSIONS: The results strongly suggest that glutamine dipeptide-containing total parenteral nutrition prevents intestinal atrophy and increased permeability associated with glutamine-free parenteral nutrition.

Aged↗
PubMed1993

Electrochemical detection of dipeptides with selectivity against amino acids.

Electrolysis of a basic mobile phase containing biuret reagent [Cu(II) and a tartrate salt] at high (> 1.2 V vs. Ag/AgCl) potentials modifies the glassy carbon electrode. This modified anode oxidizes dipeptides, yielding signals expected for a one-electron transfer, even at low (down to 0.7 V vs. Ag/AgCl) potentials and in the absence of intentionally added copper(II) ion in the reagent or mobile phase. The same modification demonstrates a selectivity to alpha-dipeptides over amino acids that is unprecedented. The product of the anodic reaction is reduced at a downstream cathode at low positive potentials. Sensitivities for several amino acids and dipeptides are reported under several conditions. Neither the anodic nor the cathodic signals for the buiret complex of the tripeptide Ala-Ala-Ala are significantly altered because of the modification.

Amino Acid Sequence↗
PubMed1990

Reverse turns in blocked dipeptides are intrinsically unstable in water.

We have carried out molecular dynamics simulations to study the conformational equilibria of two blocked dipeptides, Ac-Ala-Ala-NHMe and trans-Ac-Pro-Ala-NHMe, in water (Ac, amino-terminal blocking group COCH3; NHMe, carboxy-terminal blocking group NHCH3). Using specialized sampling techniques we computed free-energy surfaces as functions of a conformation co-ordinate that corresponds to hydrogen-bonded reverse turns at small values and to extended conformations at large values. The free-energy difference between hydrogen-bonded reverse turn conformations and extended conformations, determined from the equilibrium constants for reverse turn unfolding, is approximately -5 kcal/mole for Ac-Ala-Ala-NHMe, and -10 kcal/mole for Ac-Pro-Ala-NHMe. These results demonstrate that reverse turns in blocked dipeptides are intrinsically unstable in water. That is, in the absence of strongly stabilizing sequence-specific inter-residue interactions involving side-chains and/or charged terminal groups, the extended conformations of small peptides are highly favored in solution. By thermodynamically decomposing the free-energy differences, we found that the peptide-water entropy is the primary reason for the exceptional stability of the extended conformations of both peptides, and that the differences between the two peptides are primarily due to differences in the peptide-water interactions. In addition, we assessed the "proline effect" on the conformational equilibria by comparing the differences in configurational entropies between the reverse turn and extended conformations of the two peptides. As expected, the extended conformation of the Pro-Ala peptide is destabilized by reduced configurational entropy, but the effect is negligible in the blocked dipeptides. Finally, we compared our results with the results of several other experimental studies to identify some of the specific interactions that may be responsible for stabilizing reverse turns in small peptides in solution.

Amino Acid Sequence↗
PubMed1983

The C-terminal dipeptide of beta-endorphin: a neuropeptide with inhibitory activity.

Glycylglutamine, the C-terminal dipeptide of beta-endorphin, has previously been shown to be present in porcine pituitary. Evidence is given that this dipeptide occurs in ovine brain stem where its concentration was shown to be similar to that of the complementary fragments of beta-endorphin determined by chromatography and radioimmunoassay. Using the technique of microiontophoresis an inhibitory activity of the dipeptide was demonstrated on neurones located in the reticular formation of rat brain stem.

Animals↗
PubMed1983

Dipeptide metabolism in the isolated perfused rat kidney.

Renal handling of glycyl-proline was studied in the isolated perfused rat kidney. Glycyl-proline disappeared from the perfusate as a function of time. The dipeptide was freely filtered at the glomerulus but only 6% of the filtered load was excreted in the urine as the intact peptide. More than 90% of the filtered dipeptide was reabsorbed as the intact peptide and/or its hydrolytic products. Non-filtration mechanisms were also involved to a significant extent in the clearance of the peptide. Hydrolysis at intratubular, intracellular and peritubular sites all contribute to the disappearance of the dipeptide from the perfusate, though the relative contributions of each mechanism are not known. Significant metabolic conversions, especially the conversion of glycine to serine, were also observed during perfusion.

Animals↗
PubMed1986

Effect of various enkephalin analogs and dipeptides on the enzymatic activity of enkephalinase B isolated from calf-brain striatum.

The inhibitory potency of several enkephalin analogs and dipeptides on the calf-brain enkephalinase B activity was established with the aim to characterize its active site. Highest potency was measured for dipeptides with a large side chain on both amino acids. The nature of the distal amino acid is of minor importance, provided it is not a glycine. Free carboxylic function is required for good interaction, whereas the stereochemical configuration of the dipeptide is less so. Enkephalinase B has only little affinity for D-Ala2-Leu-enkephalin. The data are to be used for the design of new enkephalinase B inhibitors.

Animals↗
PubMed1987

Endorphinergic modulation of immune function: potent action of the dipeptide glycyl-L-glutamine.

Glycyl-L-glutamine (GLG), the carboxy terminal dipeptide of B-endorphin, inhibits brainstem neuronal activity. It also occurs along with B-endorphin in pituitary secretory vesicles suggesting a neurosecretory role for this dipeptide. We have evaluated potential immunoregulatory actions of this compound using the Phytohemaglutinin (PHA) blastogenesis and the concanavalin A (ConA) suppressor cell induction assays. GLG in low doses (10(-12) M) enhanced the response of human lymphocytes to PHA induced blastogenesis, however; with higher doses of the dipeptide (10(-7) M) immunosuppression was consistently observed. In the suppressor cell induction assay, when GLG was used together with ConA, we observed a dose-dependent inhibition of suppressor activity. These results clearly indicate that GLG produces a dose dependent bidirectional modulation of at least two indicies of immune function, and confirm the presence of a second pituitary peptide with the potential for potent immunomodulatory action.

Concanavalin A↗
PubMed1984

Comparison of the antinociceptive effect between D-Arg containing dipeptides and tetrapeptides in mice.

D-Arg containing dipeptides, H-Tyr-D-Arg-OMe and H-Tyr (Et)-D-Arg-OMe, and D-Arg2 substituted N-terminal tetrapeptides of dermorphin, H-Tyr-D-Arg-Phe-Gly-OEt and H-Tyr (Et)-D-Arg-Phe-Gly-OEt administered intracerebroventricularly exhibited dose-dependent antinociceptive activities in mice as measured by the tail pressure and phenylbenzoquinone writhing tests. The effects of these peptides used were significantly antagonized by the pretreatment with naloxone, indicating that these effects must be produced through opioid receptors. Furthermore, it is of conspicuous interest that the effects of tetrapeptides revealed in infinitestimal order (ED50 = 12.5 and 355.0 pmole in the tail pressure test and 3.1 and 53.0 pmole in the phenylbenzoquinone writhing test, respectively) and was much more potent and prolonged than those of morphine, not to mention dipeptides used. However, judging from the difference of peak times and the degree of the antagonism by naloxone, it was suggested that dipeptides and tetrapeptides used might act on different sites of action in the central nervous system.

Analgesia↗
PubMed1985

Activating effect of the Ile-Val dipeptide on the catalytic properties of bovine trypsinogen.

The dependence of pre-steady-state and steady-state kinetics for the trypsinogen-catalyzed hydrolysis of ZArgONp on the concentration (up to 2.0 M) of the Ile-Val effector dipeptide has been investigated at pH 8.0 and 21 +/- 0.5 degrees C. Kinetic parameters for the hydrolysis of ZArgONp catalyzed by the Ile-Val:zymogen adduct are more favorable than those observed for the free proenzyme but lower than those reported for beta-trypsin; these data indicate that the effector dipeptide induces only a partial activation of the zymogen even under saturating Ile-Val concentrations. From the dependence of kinetic parameters of proenzyme catalysis on the effector dipeptide concentration, values of the equilibrium constants for binding of Ile-Val to the free trypsinogen, to the reversible zymogen-ZArgONp complex and to the proenzyme-ZArg acyl intermediate have been obtained. Thermodynamics of binding of Ile-Val to trypsinogen, in the presence and absence of substrates and inhibitors, are indicative of the presence of different activation levels of the proenzyme, none of which is superimposable on that of beta-trypsin. On this basis, it is suggested that some of these different states could correspond to those involved in the zymogen-to-active-enzyme transition, which should be considered as a multistep process, rather than an all-or-nothing event.

Animals↗