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At least 19 recordsLinked to original sources
PubMed1987

Parenteral nutrition with an amino acid solution containing a mixture of dipeptides. Evidence for efficient utilization of dipeptides in man.

Ten healthy human subjects received parenteral nutrition consisting of 80 g of a dipeptide-amino acid mixture and 900 carbohydrate calories infused over a period of 12 h, and then fasted for another period of 12 h. The dipeptides included in the mixture were: glycyl-L-glutamine, glycyl-L-tyrosine, glycyl-L-leucine, glycyl-L-isoleucine, and glycyl-L-valine. Parenteral nutrition with the dipeptide-amino acid mixture was without any adverse reaction in any of the subjects. The urinary excretion of the 5 dipeptides during parenteral nutrition ranged between 1 and 2% of the amount infused. Plasma concentrations of dipeptides during parenteral nutrition, which ranged from 8-96 microM reflected their plasma half-lives. Glycyl-L-glutamine had the longest half-life, glycyl-L-leucine and glycyl-L-tyrosine the shortest half-lives. During parenteral nutrition there were increases in plasma amino acid concentrations including those of glutamine and tyrosine. Discontinuation of parenteral nutrition resulted in the disappearance of dipeptides from plasma, and the dissipation of increased plasma amino acid concentrations. In conclusion, the present results show efficient utilization of glycyl-dipeptides as substrates for parenteral nutrition in man. The results further show that the structure of amino acids in the C-terminal position has a significant influence on the metabolism of dipeptides.

Adult↗
PubMed1990

Electrochemical detection of dipeptides and dipeptide amides.

A postcolumn reagent is used to create electroactive species from non-electroactive peptides. The reagent, based on the classical biuret reagent, consists of Cu(II), tartrate, bicarbonate and base. The detection is by dual electrode electrochemical detection. N-Acetylated dipeptides are oxidized at pH 12 and low potential. Dipeptides and carboxy terminal dipeptide amides give useful signals at lower pH. The dipeptide amides react with Cu(II) as do the tripeptides to yield the electronic spectrum and electrochemistry of the biuret complex. The complexes formed from the dipeptides are reversibly oxidized at potentials greater than 0.85 V vs. Ag/AgCl, 3 M NaCl. Analytically useful signals are obtained for the dipeptide amides at sensitivities equivalent to the sensitivities for longer peptides, 3-5 nA/microM, while the sensitivities for the dipeptides are about an order of magnitude lower.

Amides↗
PubMed1990

Intestinal absorption of dipeptides and beta-lactam antibiotics. II. Purification of the binding protein for dipeptides and beta-lactam antibiotics from rabbit small intestinal brush border membranes.

By photoaffinity labeling of brush border membrane vesicles from rabbit small intestine with photoreactive derivatives of beta-lactam antibiotics and dipeptides, a binding protein for dipeptides and beta-lactam antibiotics with an apparent molecular weight of 127,000 was labeled. The labeled 127 kDa polypeptide could be solubilized with the non-ionic detergents Triton X-100, n-octyl glucoside or CHAPS. If the vesicles were solubilized prior to photoaffinity labeling, no clear incorporation of radioactivity into the 127 kDa polypeptide occurred indicating a loss of binding ability upon solubilization. By affinity chromatography of solubilized brush border membrane proteins on an agarose wheat germ lectin column, the binding protein for dipeptides and beta-lactam antibiotics of Mr 127,000 was retained on the column. With N-acetyl-D-glucosamine the photolabeled binding protein for beta-lactam antibiotics and dipeptides was eluted together with the brush border membrane-bound enzyme aminopeptidase N. Separation from aminopeptidase N and final purification was achieved by anion-exchange chromatography on DEAE-sephacel. Polyclonal antibodies against the purified binding protein were raised in guinea pigs. The photolabeled 127 kDa protein could be precipitated from solubilized brush border membranes with these antibodies. Incubation of brush border membrane vesicles with antiserum prior to photoaffinity labeling significantly reduced the extent of labeling of the 127 kDa protein. Treatment of brush border membrane vesicles with antiserum significantly inhibited the efflux of the alpha-aminocephalosporin cephalexin from the brush border membrane vesicles compared to vesicles treated with preimmune serum. These studies indicate that the binding protein for dipeptides and beta-lactam antibiotics of apparent molecular weight 127,000 in the brush border membrane of rabbit small intestinal enterocytes is directly involved in the uptake process of small peptides and orally active beta-lactam antibiotics across the enterocyte brush border membrane.

Affinity Labels↗
PubMedDate not supplied

A third dipeptide carrier system typified by l-prolyl-lhydroxyproline and independent of l-leucyl and beta-alanyl dipeptides in rat gut loops.

1. The intestinal transport of L-prolyl-L-hydroxyproline (10 mmol/l) was investigated in rat small gut loops in vivo under pentobarbitone anaesthesia. Osmolality of test solutions was adjusted to eliminate any positive effect of solvent drag on disappearance of solutes from the lumen. 2. L-Leucylglycine and beta-alanyl-L-histidine (carnosine), representative members of two distinctly different dipeptide transport groups previously delineated, were tested for competitive action on L-prolyl-L-hydroxyproline uptake at ten times equimolar concentration (100 mmol/l), but were found to have no effect on the carrier system. 3. L-Prolyl-L-hydroxyproline uptake was markedly blocked by other L-prolyl dipeptides, indicating that they shared a common carrier system. Disappearance of L-prolyl-L-hydroxyproline from the gut lumen was reduced from 48% 15 min-1 10 cm-1 (control, containing 70 mmol/l mannitol) to 11% or 20% in the presence of L-prolylglycine (100 mmol/l) or L-prolyl-L-leucine (25 mmol/l), respectively. 4. It was concluded that at least three separate dipeptide carrier protein systems exist in the rat small gut, the disappearance of L-prolyl-L-hydroxyproline from the gut lumen being inhibited by two other L-prolyl dipeptides but not by L-leucyl or beta-alanyl dipeptides.

Alanine↗
PubMed1985

Marked enhancement in vivo of adjuvant activity of muramyl dipeptide to protein antigens and to synthetic weak immunogens with monoclonal anti-muramyl dipeptide antibodies.

Priming of mice with complexes of antigen coupled to muramyl dipeptide and monoclonal anti-muramyl dipeptide antibodies enhanced the adjuvant activity of muramyl dipeptide on the humoral response to the antigen. The enhancement did not occur with free (uncoupled) muramyl dipeptide and required the presence of an adjuvant-active hapten within the complex as well as the Fc fragment of the monoclonal antibody. This system proved highly effective in eliciting antibodies to synthetic weak immunogens whereas muramyl dipeptide, on its own, exerts very little or no adjuvant activity. The effect was not due to a general polyclonal activation and was restricted to the antigen coupled to the synthetic adjuvant. Possible pathways involved in this phenomenon are discussed.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1991

Peptide transport and chemotaxis in Escherichia coli and Salmonella typhimurium: characterization of the dipeptide permease (Dpp) and the dipeptide-binding protein.

The dipeptide permease (Dpp) is one of three genetically distinct peptide-transport systems in enteric bacteria. Dpp also plays a role in chemotaxis towards peptides. We have devised three selections for dpp mutations based on resistance to toxic peptides (bacilysin, valine-containing peptides, and bialaphos). All dpp mutations mapped to a single chromosomal locus between 77 and 78 min in Salmonella typhimurium and at 79.2 min in Escherichia coli. Expression of dpp was constitutive in both species but the absolute level of expression varied widely between strains. At least in part this difference in expression levels is determined by cis-acting sequences. The dpp locus of E. coli was cloned. The first gene in the operon, dppA, encodes a periplasmic dipeptide-binding protein (DBP) required for dipeptide transport and chemotaxis. Downstream of dppA are other genes required for transport but not for chemotaxis. The dipeptide-binding protein was found to share 26.5% sequence identity with the periplasmic oligopeptide-binding protein OppA.

Amino Acid Sequence↗
PubMed1989

Conformational perturbations in retro-analogs of the tBuCO-Ala-Gly-NHiPr dipeptide. Crystal structure of the retro-dipeptide with a reversed Ala-Gly amide bond.

The three retro-analogs of the tBuCO-Ala-Gly-NHiPr dipeptide, in which each amide bond had been successively reversed, were studied in solution by 1H-n.m.r. and i.r. spectroscopy with reference to the conformational properties of their parent dipeptide. Reversal of the Ala-Gly amide bond proved to perturb the folding tendency of the backbone less than the inversion of either of the terminal amide bonds. The crystal structure of the retro-peptide containing a reversed Ala-Gly amide bond was also solved by X-ray diffraction and constitutes the first available data for this retro-peptide series. In contrast to the beta II-folded structure of the parent dipeptide, the retro-peptide molecule adopts an open conformation in the crystal.

Dipeptides↗
PubMed1992

Analgesic dipeptide derivatives. 7. 3,7-Diamino-2-hydroxyheptanoic acid (DAHHA) containing dipeptide analogues of the analgesic compound H-Lys-Trp(Nps)-OMe.

A series of diastereomeric dipeptides, analogues of the analgesic compound H-Lys-Trp(Nps)-OMe (2), containing 3,7-diamino-2-hydroxyheptanoic acid (DAHHA) and 2-[(o-nitrophenyl)sulfenyl]tryptophan [Trp(Nps)] has been synthesized. These compounds were tested as enkephalin-degrading aminopeptidases (APs), AP-M and AP-B inhibitors, and analgesics. The inhibitory potencies and the antinociceptive effects depended on the stereochemistry of the compounds. (2S,3R)-DAHHA-L-Trp(Nps)-OMe (26d) was a highly potent and selective enkephalin-degrading APs inhibitor, with an IC50 value in the 10(-8) M range. Although this derivative was about 10(3)-fold more potent than 2 against these enzymes, their antinociceptive effects were completely similar. These results indicate that the inhibitory capacity of this series of Trp(Nps)-containing dipeptides against enkephalin-degrading enzymes is not an important factor for their antinociceptive effects.

Aminopeptidases↗
PubMed1988

Analgesic activity of two synthetic immunomodulators, muramyl dipeptide and adamantylamide dipeptide in mice and rats.

The potency of two synthetic immunomodulators, muramyl dipeptide and adamantylamide dipeptide, which have the immunoadjuvant and immunomodulatory activity on pain threshold was studied. Two different analgesiometric procedures were employed: hot plate test and acetic acid writhing test in mice and rats. Both compounds were injected intravenously (1-4 mg/kg), intraperitoneally (5-50 mg/kg) and intracerebroventricularly (0.5-4 mg/kg) and were able to produce mild transient analgesia in both species. Writhing response was more influenced after systemic administration of drugs while hot plate latencies was not. On the contrary, latencies in hot plate test were more affected than the writhing response after intracerebroventricular administration. Dose response curve showed a bell shaped feature typical for peptides. Pretreatment with naltrexone, an opiate antagonist, did not prevent the analgesic action of tested compounds. The hyperalgesia induced by administration of parachlorophenylalanine, a serotonin depletor, could be prevented by administration of a nonanalgesic dose of MDP (0.025 mg/kg). At higher dosages (1 mg/kg) MDP was able to antagonize also general toxic effects of pCPA. These results support the possibility of participation of central serotonergic structures in MDP and AdDP induced analgesia. The peripheral mechanism of action, however, can not be completely ruled out.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1987

Analgesic dipeptide derivatives. II. Synthetic dipeptides containing a C-terminal 2-(2-nitrophenylsulfenyl) tryptophan residue.

The syntheses of dipeptide derivatives of the general formula X-Trp(Nps)-OR (R = H or Me; X = Lys, Gly, Ala, Leu, Ser, Glu, His, Arg, Orn, Dpr, Gpr and Har) are described. The analgesic activities of Gpr- and Har-containing dipeptides have been evaluated and, in the light of these results, the influence of the side chain length of the basic amino acid on the analgesic effect is studied.

Analgesia↗
PubMed1990

Intestinal uptake of dipeptides and beta-lactam antibiotics. I. The intestinal uptake system for dipeptides and beta-lactam antibiotics is not part of a brush border membrane peptidase.

The uptake of beta-lactam antibiotics into small intestinal enterocytes occurs by the transport system for small peptides. The role of membrane-bound peptidases in the brush border membrane of enterocytes from rabbit and pig small intestine for the uptake of small peptides and beta-lactam antibiotics was investigated using brush border membrane vesicles. The enzymatic activity of aminopeptidase N was inhibited by beta-lactam antibiotics in a non-competitive manner whereas dipeptidylpeptidase IV was not affected. The peptidase inhibitor bestatin led to a strong competitive inhibition of aminopeptidase N whereas the uptake of cephalexin into brush border membrane vesicles was only slightly inhibited at high bestatin concentrations (greater than 1 mM). Modification of brush border membrane vesicles with the histidine-modifying reagent diethyl pyrocarbonate led to a strong irreversible inhibition of cephalexin uptake whereas the activity of aminopeptidase N remained unchanged. A modification of serine residues with diisopropyl fluorophosphate completely inactivated dipeptidylpeptidase IV whereas the transport activity for cephalexin and the enzymatic activity of aminopeptidase N were not influenced. With polyclonal antibodies raised against aminopeptidase N from pig renal microsomes the aminopeptidase N from solubilized brush border membranes from pig small intestine could be completely precipitated; the binding protein for beta-lactam antibiotics and oligopeptides of apparent Mr 127,000 identified by direct photoaffinity labeling with [3H]benzylpenicillin showed no crossreactivity with the aminopeptidase N anti serum and was not precipitated by the anti serum. These results clearly demonstrate that peptidases of the brush border membrane like aminopeptidase N and dipeptidylpeptidase IV are not directly involved in the intestinal uptake process for small peptides and beta-lactam antibiotics and are not a constituent of this transport system. This suggests that a membrane protein of Mr 127,000 is (a part of) the uptake system for beta-lactam antibiotics and small peptides in the brush border membrane of small intestinal enterocytes.

Affinity Labels↗
PubMed1991

Pharmacokinetic profile of the immunomodulating compound adamantylamide dipeptide (AdDP), a muramyl dipeptide derivative in mice.

A pharmacokinetic profile of 14C-AdDP with uniformly labelled alanine was investigated. It was shown that the distribution phase after an i.v. administration is very short with a half-life of 2.1 min. The half-life of elimination phase after the i.v. administration is about 2.85 hours, that is longer than those of MDP and its derivatives. The total body clearance (30 ml/min/kg) is caused predominantly by metabolism of the compound. All the radioactivity found in urine in a 48 hours interval after a s.c. administration represents only 3.1% of the administered dose. Only a smaller part of the excreted radioactivity is formed by unmetabolised AdDP. The concentration curve after a s.c. administration is characterized by a very fast absorption with a half-life shorter than 1 minute. The distribution and elimination phases are prolonged (20 min, 11 hours respectively) in comparison with an i.v. injection. The decreased absolute bioavailability after a s.c. administration (65%) is probably not biologically significant because of a slower release of the compound from the site of the s.c. administration. A relatively very high radioactivity was found in liver, kidney, thymus, spleen and brain very soon which suggest a very good penetration into tissues. It is an agreement with the high apparent distribution volume of peripheral compartment and higher lipophilicity of AdDP as compared to MDP.

Adjuvants, Immunologic↗
PubMed1989

[Immunostimulating effects of muramyl dipeptide, glucosaminyl muramyl dipeptide and their synthetic derivatives in vitro].

The effect of muramyldipeptide (MDP), glucosaminylmuramyldipeptide (GMDP) and their six synthetic derivatives on production of tumor necrosis factor (TNF), interleukin-1 (IL-1) and interleukin-2 (IL-2) by murine spleen cells in vitro was studied. MDP induced insignificant TNF production and did not stimulate production of IL-1 by the murine splenocytes within a 24-hour cultivation period whereas in combination with lipopolysaccharide (LPS) it induced significant production of both the cytokins. GMDP induced marked production of TNF (54 per cent cytotoxic index) and IL-1 (stimulation index 8). Addition of LPS in an amount of 10 ng/ml increased production of TNF by the murine splenocytes under the effect of GMDP but had no effect on production of IL-1. Neither MDP nor GMDP even in combination with LPS induced production of IL-2 by splenocytes of mice DVA/2 and C57B1/6 at activation for 24 hours. All the synthetic derivatives of MDP and GMDP except the MDP polymer activated TNF production by the murine spleen cells. GMDP lysine had the highest effect: 67 per cent cytotoxic index. In combination with LPS its cytotoxic index amounted to 87 per cent. The TNF activity was always higher when LPS in an amount of 10 ng/ml was added to the glycopeptides.

Acetylmuramyl-Alanyl-Isoglutamine↗