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PubMed2005

On the activation of valerolactam with triflic anhydride: the synthesis of omega-trifluorosulfonamido dipeptides using a transpeptidation reaction under mild conditions.

The activation of valerolactam with triflic anhydride is studied in detail, initially producing an O-triflated lactam, which rearranges, following the addition of base at higher temperatures, to an N-triflated derivative. This reacts with a series of nucleophiles to produce esters and amides, which are formally dipeptides of omega-amino acids.

Anhydrides↗
PubMed2005

Asymmetric conjugate reductions with samarium diiodide: asymmetric synthesis of (2S,3R)- and (2S,3S)-[2-2H,3-2H]-leucine-(S)-phenylalanine dipeptides and (2S,3R)-[2-(2)H,3-2H]-phenylalanine methyl ester.

The highly diastereoselective samarium diiodide and D(2)O-promoted conjugate reduction of homochiral (E)- and (Z)-benzylidene and isobutylidene diketopiperazines (E)-5,7 and (Z)-6,8 has been demonstrated. This methodology allows the asymmetric synthesis of methyl (2S,3R)-dideuteriophenylalanine 27 in > or = 95% de and >98% ee, and (2S,3R)- or (2S,3S)-dideuterioleucine-(S)-phenylalanine dipeptides 37 and 38 in moderate de, 66% and 74% respectively. A mechanism is proposed to account for this process.

Crystallography, X-Ray↗
PubMed2002

Boilysin and thermolysin in dipeptide synthesis: a comparative study.

Boilysin (BLN) is an engineered, highly thermostable neutral protease from Bacillus stearothermophilus. Its high resistance is based on the stabilization of a surface loop (amino acid residues 55-69) by eight amino acid exchanges, including the introduction of a disulphide bond. In the present study, BLN was compared with the well-known and structurally related thermolysin (from B. thermoproteolyticus) with respect to their dipeptide- synthetic properties. The synthesis of the aspartame precursor N-(benzyloxycarbonyl)-l-aspartyl-l-phenylalanine methyl ester (Z-Asp-Phe-OMe) was used as the model reaction to study its enantioselectivity as well as the influence of neutral salt, temperature and calcium- ion concentration on peptide synthesis. The reactions were performed in homogeneous reaction systems containing DMSO or aliphatic alcohols. Furthermore, the substrate specificity in the synthesis of Z-Asp-X-OMe (X=Phe, d-Phe, Ala, Ile, Leu, Met, Tyr or Val) was examined. The two enzymes showed no difference in time course of reaction by the use of salts as activators or different alcohols as co-solvents. Both enzymes showed a high enantioselectivity towards the amino component in the reaction. They were strongly activated by NaCl, whereas the final product yields were strongly decreased at high NaCl concentrations. Aliphatic alcohols act as an inhibitor, but allow higher product yields compared with purely aqueous medium. Differences between the two enzymes are found at higher temperatures (>/=60 degrees C) in the absence or at low concentrations of Ca(2+) ions; BLN proved superior under these conditions, because its stability is less dependent on Ca(2+) ions. The substrate specificities of BLN and thermolysin at the P(')(1) position follow the same tendencies, with differences in the initial rates for the conversion of Z-Asp with Ile-OMe, Leu-OMe and Val-OMe.

Alcohols↗
PubMed2005

Kinetic investigation of human dipeptidyl peptidase II (DPPII)-mediated hydrolysis of dipeptide derivatives and its identification as quiescent cell proline dipeptidase (QPP)/dipeptidyl peptidase 7 (DPP7).

The presence of DPPII (dipeptidyl peptidase II; E.C. 3.4.14.2) has been demonstrated in various mammalian tissues. However, a profound molecular and catalytic characterization, including substrate selectivity, kinetics and pH-dependence, has not been conducted. In the present study, DPPII was purified from human seminal plasma to apparent homogeneity with a high yield (40%) purification scheme, including an inhibitor-based affinity chromatographic step. The inhibitor lysyl-piperidide (K(i) approximately 0.9 microM at pH 5.5) was chosen, as it provided a favourable affinity/recovery ratio. The human enzyme appeared as a 120 kDa homodimer. Mass spectrometric analysis after tryptic digestion together with a kinetic comparison indicate strongly its identity with QPP (quiescent cell proline dipeptidase), also called dipeptidyl peptidase 7. pH profiles of both kcat and kcat/K(m) clearly demonstrated that DPPII/QPP possesses an acidic and not a neutral optimum as was reported for QPP. Kinetic parameters of the human natural DPPII for dipeptide-derived chromogenic [pNA (p-nitroanilide)] and fluorogenic [4Me2NA (4-methoxy-2-naphthylamide)] substrates were determined under different assay conditions. DPPII preferred the chromogenic pNA-derived substrates over the fluorogenic 4Me2NA-derived substrates. Natural human DPPII showed high efficiency towards synthetic substrates containing proline at the P1 position and lysine at P2. The importance of the P1' group for P2 and P1 selectivity was revealed, explaining many discrepancies in the literature. Furthermore, substrate preferences of human DPPII and dipeptidyl peptidase IV were compared based on their selectivity constants (kcat/K(m)). Lys-Pro-pNA (k(cat)/K(m) 4.1x10(6) s(-1) x M(-1)) and Ala-Pro-pNA (kcat/K(m) 2.6x10(6) s(-1) x M(-1)) were found to be the most sensitive chromogenic substrates for human DPPII, but were less selective than Lys-Ala-pNA (kcat/K(m) 0.4x10(6) s(-1) x M(-1)).

Amino Acid Sequence↗
PubMed1987

Effects of sodium replacement on uptake of the dipeptide glycylsarcosine by hamster jejunum in vitro.

We report observations on transport of the hydrolysis-resistant dipeptide glycylsarcosine by rings of everted hamster jejunum in vitro in the presence and absence of Na+, using several substituents for Na+: Li+, K+, Cs+, Tris, choline and mannitol. At most concentrations, mediated influx of glycylsarcosine was depressed by Li+, K+, Cs+ and Tris, though not abolished. At high concentrations, it was moderately increased by choline and mannitol. Under conditions in which the tissue could concentrate the peptide in the presence of Na+, uptake was greatly depressed by all the substituents and the ability to concentrate was abolished. The Kt of mediated influx was affected in different ways according to the substituent used. Kt was reduced by Li+ replacement of Na+ and increased by choline replacement. Vmax was greatly reduced by all metallic substituents but not by non-metallic substituents. Though the results cannot yet be satisfactorily interpreted, they suggest possible reasons for previous conflicting results and show that it is impossible to make the unqualified statement that transport of glycylsarcosine is 'Na+-dependent'. It is now doubtful whether transport of this peptide into the intestinal cells is by co-transport with Na+, and the whole matter of Na+-dependence of intestinal peptide transport is in question.

Animals↗
PubMed2002

Dipeptide utilization by the periodontal pathogens Porphyromonas gingivalis, Prevotella intermedia, Prevotella nigrescens and Fusobacterium nucleatum.

Porphyromonas gingivalis, Prevotella intermedia, Prevotella nigrescens and Fusobacterium nucleatum, which can frequently be isolated from periodontal pockets, preferentially utilize proteins and peptides as growth substrates. In this study, we determined the size of peptide that is preferentially utilized as a source of energy and material for cell growth by P. gingivalis, P. intermedia, P. nigrescens and F. nucleatum using various sizes of poly amino acids consisting of two to approximately 100 molecules of aspartate or glutamate. Resting cells of P. gingivalis, P. intermedia and P. nigrescens utilized aspartylaspartate, while cells of P. gingivalis and F. nucleatum utilized glutamylglutamate. The addition of aspartylaspartate to the culture medium increased the growth of P. gingivalis, P. intermedia and P. nigrescens, while the addition of glutamylglutamate promoted the growth of P. gingivalis and F. nucleatum. These results clearly indicate that dipeptides such as aspartylaspartate and glutamylglutamate can be utilized as growth substrates for P. gingivalis, P. intermedia, P. nigrescens and F. nucleatum.

Aspartic Acid↗
PubMed1997

The dipeptide repeat region of the fibrinogen-binding protein (clumping factor) is required for functional expression of the fibrinogen-binding domain on the Staphylococcus aureus cell surface.

Clumping factor of Staphylococcus aureus is a fibrinogen-binding protein that is located on the bacterial cell surface. The protein has an unusual repeat domain (region R) comprising mainly the dipeptide aspartate and serine. To determine if region R has a role in the surface display of the fibrinogen-binding region A domain, deletions lacking the region R encoding region of the clfA gene were generated. To determine the minimum length of region R required for wild-type levels of ClfA expression, variants with truncated region R domains were constructed. S. aureus cells expressing mutated clfA genes were tested for (i) proteins released by lysostaphin treatment that reacted with antisera specific for region A, (ii) clumping in soluble fibrinogen, (iii) adherence to immobilized fibrinogen and (iv) expression of the ClfA antigen on the cell surface by fluorescent activated cell sorting analysis. Each construct expressed three major immunoreactive proteins, two of which were putative N-terminal degradation products. Region R residues greater than 40 were required between region A and W (72 residues between region A and the LPDTG sorting signal) for wild-type levels of clumping in fibrinogen. A stepwise decrease in clumping titre was observed as the distance between region A and LPDTG was decreased from 72 to 4 residues. Similarly, a decrease in binding of anti-ClfA serum and in binding to fibrinogen-coated plastic surfaces was observed with cells expressing ClfA with 40 region R residues or less. Nevertheless, low levels of adherence to fibrinogen and binding to anti-ClfA serum occurred with ClfA derivatives that lacked region R altogether. This indicates that a small proportion of the ClfA molecules are linked to peptidoglycan very close to the cell surface but that residues greater than 72 are needed to allow sufficient ClfA molecules to span the entire cell wall and to display the biologically active A domain in a form that can participate fully in fibrinogen binding.

Binding Sites↗
PubMed1999

Identification of dipeptide repeats and a cell wall sorting signal in the fimbriae-associated adhesin, Fap1, of Streptococcus parasanguis.

Fap1, a fimbriae-associated protein, is involved in fimbriae assembly and adhesion of Streptococcus parasanguis FW213 (Wu et al., 1998). In this study, the sequence of the fap1 gene was resolved using a primer island transposition system. Sequence analysis indicated that fap1 was composed of 7659 nucleotides. The predicted Fap1 protein contains an unusually long signal sequence (50 amino acid residues), a cell wall sorting signal and two repeat regions. Repeat regions I and II have a similar dipeptide composition (E/V/I)S, composed of 28 and 1000 repeats respectively. The two regions combined accounted for 80% of the Fap1 coding region. The experimental amino acid composition and isoelectric point (pI) of Fap1 were similar to that predicted from the deduced Fap1 protein. Results of Northern analyses revealed that the fap1 open reading frame (ORF) was transcribed as a 7.8 kb monocistronic message. Insertional inactivation at the 3' end, downstream of the fap1 ORF, did not affect Fap1, fimbrial expression or bacterial adhesion. Insertional inactivation of fap1 immediately upstream of the repeat region II abolished expression of Fap1 and fimbriae, and was concurrent with a diminution in adhesion of FW213. Inactivation of the cell wall sorting signal of fap1 also eliminated long fimbrial formation and reduced the ability of FW213 to bind to SHA. Fap1 was no longer anchored on the cell surface. Large quantities of truncated Fap1 were found in the growth medium instead. These results suggest that the fap1 ORF alone is sufficient to support Fap1 expression and adhesion, and demonstrate that anchorage of Fap1 on the cell surface is required for long fimbriae formation. These data further document the role of long fimbriae in adhesion of S. parasanguis FW213 to SHA.

Adhesins, Bacterial↗
PubMed1999

Hydrolysis by somatic angiotensin-I converting enzyme of basic dipeptides from a cholecystokinin/gastrin and a LH-RH peptide extended at the C-terminus with gly-Arg/Lys-arg, but not from diarginyl insulin.

Endoproteolytic cleavage of protein prohormones often generates intermediates extended at the C-terminus by Arg-Arg or Lys-Arg, the removal of which by a carboxypeptidase (CPE) is normally an important step in the maturation of many peptide hormones. Recent studies in mice that lack CP activity indicate the existence of alternative tissue or plasma enzymes capable of removing C-terminal basic residues from prohormone intermediates. Using inhibitors of angiotensin I-converting enzyme (ACE) and CP, we show that both these enzymes in mouse serum can remove the basic amino acids from the C-terminus of CCK5-GRR and LH-RH-GKR, but only CP is responsible for converting diarginyl insulin to insulin. ACE activity removes C-terminal dipeptides to generate the Gly-extended peptides, whereas CP hydrolysis gives rise to CCK5-GR and LH-RH-GK, both of which are susceptible to the dipeptidyl carboxypeptidase activity of ACE. Somatic ACE has two similar protein domains (the N-domain and the C-domain), each with an active site that can display different substrate specificities. CCK5-GRR is a high-affinity substrate for both the N-domain and C-domain active sites of human sACE (Km of 9.4 microm and 9.0 microm, respectively) with the N-domain showing greater efficiency (kcat : Km ratio of 2.6 in favour of the N-domain). We conclude that somatic forms of ACE should be considered as alternatives to CPs for the removal of basic residues from some Arg/Lys-extended peptides.

Animals↗
PubMed2002

Val-Tyr as a natural antihypertensive dipeptide can be absorbed into the human circulatory blood system.

1. Intact absorption of the bioactive dipeptide Val-Tyr (VY), with in vivo antihypertensive ability in normotensive human subjects, was investigated. 2. As a result of a single oral administration of VY, the VY absorption curve occurred maximally over the second hour postprandially; a greater than 10-fold higher increment of VY following a dose of 12 mg was observed in the plasma at 2 h compared with the baseline concentration of VY at 0 h (1934 +/- 145 vs 159 +/- 11 fmol/mL plasma, respectively). 3. Plasma VY levels increased with dose administered (3, 6 and 12 mg), suggesting that exogenous VY could be absorbed intact into the human blood depending on the dose. The elimination half time (t1/2) of VY was estimated to be 3.1 h. The area under the curve for the 12 mg VY dose was 9185 +/- 688 fmol small middle doth/mL plasma.

Absorption↗
PubMed2003

Depressor effect induced by dipeptide, Val-Tyr, in hypertensive transgenic mice is due, in part, to the suppression of human circulating renin-angiotensin system.

1. In the present study, the depressor action of the dipeptide Val-Tyr, with an in vivo antihypertensive effect, was investigated in transgenic mice carrying the human renin gene cross-mated with mice bearing the human angiotensinogen gene (Tsukuba Hypertensive Mouse; THM). 2. Single oral administration of Val-Tyr (0.1 mg/g) to 11-week-old THM resulted in a prolonged reduction of blood pressure for up to 9 h. The effect clearly demonstrated that the Val-Tyr absorbed acted on the enhanced human renin-angiotensin system (RAS). 3. After Val-Tyr administration, an approximate eightfold higher increment of plasma Val-Tyr was observed at 1 h (3406 +/- 211 fmol/mL plasma) compared with the level observed at 0 h; plasma concentrations of Val-Tyr returned to baseline levels at 6 h. 4. Transient changes in plasma concentrations of angiotensin (Ang) I and AngII only at 1 h were consistent with plasma Val-Tyr concentrations, suggesting that that the long-lasting reduction in blood pressure was achieved by the latent hypotensive mechanism of Val-Tyr and not by transient suppression of the circulatory RAS. 5. Ageing of the THM greatly affected the depressor action of Val-Tyr, with no significant reduction in blood pressure observed in 18- and 24-week-old THM.

Aging↗
PubMed1998

MDP(Lysyl)GDP, a nontoxic muramyl dipeptide derivative, inhibits cytokine production by activated macrophages and protects mice from phorbol ester- and oxazolone-induced inflammation.

High levels of pro-inflammatory cytokines and nitric oxide are proposed to orchestrate pathophysiologic mechanism(s) associated with various inflammatory dermatoses. This study examines whether a water soluble 3-O-[N-acetylmuramyl-L-lysyl-D-iso]-2-di-on-glycine [MDP(Lysyl)GDP], a nontoxic and nonpyrogenic derivative of muramyl dipeptide (MDP), can inhibit the in vitro production of inflammatory mediators by lipopolysaccharide- or interferon-gamma-activated macrophages, and whether such an inhibitory effect can translate into in vivo protection of mice from irritant and allergic contact dermatitis. Thioglycollate-elicited peritoneal macrophages cultured in medium alone or in medium supplemented with MDP(Lysyl)GDP (1-100 microg per ml) expressed neither mRNA transcripts for inducible nitric oxide synthase, interleukin-1beta, and tumor necrosis factor-alpha, nor cytokine proteins and nitric oxide activity. Incubation of the cells with either lipopolysaccharide or interferon-gamma for 6 h resulted in a significant induction of inducible nitric oxide synthase, interleukin-1beta, and tumor necrosis factor-alpha mRNA, and the accumulation of high levels of monokines and nitrites in cultures by 24 h. Co-incubation of the macrophages with lipopolysaccharide or interferon-gamma and MDP(Lysyl)GDP (1-100 microg per ml) resulted in a concentration-dependent suppression of the steady-state mRNA transcripts for inducible nitric oxide synthase, tumor necrosis factor-alpha, and interleukin-1beta, induced by lipopolysaccharide, but not by interferon-gamma. In mouse models of phorbol ester- and oxazolone-induced ear inflammation, topical application of MDP(Lysyl)GDP significantly suppressed ear swelling in a dose-dependent manner. Likewise, oral treatment with MDP(Lysyl)GDP at days -3, -2, and -1 before elicitation with oxazolone also significantly inhibited ear inflammation. Taken together, our findings suggest that MDP(Lysyl)GDP has the potential to be a therapeutic application in the treatment of inflammatory conditions in which overproduction of pro-inflammatory mediators are implicated to play a pathogenic role.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1994

[Safety and tolerance of a new dipeptide-containing amino acid solution DP-Gln 20 versus a conventional amino acid solution Vamin 18EF in patients after elective colon surgery].

OBJECTIVE AND METHODS: Recent studies have demonstrated the important role of glutamine in postoperative metabolism. Using dipeptide-containing amino acid solutions it is possible to enhance glutamine supply. Safety and tolerance of DP-Gln 20 (gly-gln, gly-tyr) and Vamin 18EF were investigated in an open, prospective, randomised study. 16 patients received isonitrogenous parenteral nutrition over 4 days. RESULTS: There was no difference in clinical and biochemical patterns between both groups. Complications and adverse events due to the infused amino acid solutions were not observed.

Adolescent↗
PubMed2004

Amide I vibrational circular dichroism of dipeptide: Conformation dependence and fragment analysis.

The amide I vibrational circular dichroic response of alanine dipeptide analog (ADA) was theoretically investigated and the density functional theory calculation and fragment analysis results are presented. A variety of vibrational spectroscopic properties, local and normal mode frequencies, coupling constant, dipole, and rotational strengths, are calculated by varying two dihedral angles determining the three-dimensional ADA conformation. Considering two monopeptide fragments separately, we show that the amide I vibrational circular dichroism of the ADA can be quantitatively predicted. For several representative conformations of the model ADA, vibrational circular dichroism spectra are calculated by using both the density functional theory calculation and fragment analysis methods.

Amides↗
PubMed2005

Secondary structures of short peptide chains in the gas phase: double resonance spectroscopy of protected dipeptides.

The conformational structure of short peptide chains in the gas phase is studied by laser spectroscopy of a series of protected dipeptides, Ac-Xxx-Phe-NH(2), Xxx=Gly, Ala, and Val. The combination of laser desorption with supersonic expansion enables us to vaporize the peptide molecules and cool them internally; IR/UV double resonance spectroscopy in comparison to density functional theory calculations on Ac-Gly-Phe-NH(2) permits us to identify and characterize the conformers populated in the supersonic expansion. Two main conformations, corresponding to secondary structures of proteins, are found to compete in the present experiments. One is composed of a doubly gamma-fold corresponding to the 2(7) ribbon structure. Topologically, this motif is very close to a beta-strand backbone conformation. The second conformation observed is the beta-turn, responsible for the chain reversal in proteins. It is characterized by a relatively weak hydrogen bond linking remote NH and CO groups of the molecule and leading to a ten-membered ring. The present gas phase experiment illustrates the intrinsic folding properties of the peptide chain and the robustness of the beta-turn structure, even in the absence of a solvent. The beta-turn population is found to vary significantly with the residues within the sequence; the Ac-Val-Phe-NH(2) peptide, with its two bulky side chains, exhibits the largest beta-turn population. This suggests that the intrinsic stabilities of the 2(7) ribbon and the beta-turn are very similar and that weakly polar interactions occurring between side chains can be a decisive factor capable of controlling the secondary structure.

Amino Acids↗
PubMed2005

Transition pathways in complex systems: Application of the finite-temperature string method to the alanine dipeptide.

The finite-temperature string method proposed by E, et al. [W. E, W. Ren, and E. Vanden-Eijnden, Phys. Rev. B 66, 052301 (2002)] is a very effective way of identifying transition mechanisms and transition rates between metastable states in systems with complex energy landscapes. In this paper, we discuss the theoretical background and algorithmic details of the finite-temperature string method, as well as the application to the study of isomerization reaction of the alanine dipeptide, both in vacuum and in explicit solvent. We demonstrate that the method allows us to identify directly the isocommittor surfaces, which are approximated by hyperplanes, in the region of configuration space where the most probable transition trajectories are concentrated. These results are verified subsequently by computing directly the committor distribution on the hyperplanes that define the transition state region.

Alanine↗