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At least 685 records · Page 38Linked to original sources

PubMed1992

Influence of tyrosine on the dual electrode electrochemical detection of copper(II)-peptide complexes.

The bluret reaction makes peptides electrochemically active. This is the basis of an electrochemical method for the detection of peptides following their liquid chromatographic separation. This paper discusses the influence of tyrosine, an electroactive amino acid, on the detection of Cu(II)-peptide (bluret) complexes containing it. The dual electrode detector has an upstream anode and a downstream cathode. Tyrosine-containing peptides yield anodic signals that are approximately the sum of the tyrosine signal and the signal from the bluret complex of a nonelectroactive model peptide, phenylalanylglycyl-glycine (FGG). The cathodic signal is depressed in comparison to FGG. This is traced to the presence of an intramolecular reaction between Cu(III) and a reaction product resulting from the oxidation of the tyrosinyl residue. The rate constant for the corresponding intermolecular reaction is significant (10(6)-10(7) M-1 s-1), but in practical analytical situations, the concentrations of the reactants will be small, so the reaction will not be a major factor. Sensitivities for several bioactive peptides are reported. The dependence of the signals on the position of tyrosine in a tripeptide is also studied.

Amino Acid Sequence↗

PubMed1986

Simultaneous release of several tachykinins and calcitonin gene-related peptide from rat spinal cord slices.

Superfusion of slices of the dorsal half of rat spinal cord in vitro with 10 microM capsaicin or 60 mM potassium lead to the simultaneous release of substance P (SP)-, neurokinin A (NKA)- and calcitonin gene-related peptide (CGRP)-like immunoreactivities (LI). The ratio between capsaicin-stimulated and basal release was higher for CGRP-LI than for SP-LI, indicating that relatively more CGRP is released from sensory nerves, whereas SP is not only released from afferent neurons. High-performance liquid chromatography of NKA-LI revealed several immunoreactive components. One major peak had the retention time of synthetic NKA. A second peak eluted close to the position of synthetic eledoisin. In conclusion, capsaicin releases several bioactive peptides from sensory neurons which may mediate the acute algetic effect of chemical irritants.

Animals↗

PubMed1998

Modified chemotactic peptides: synthesis and activity of an azaTic-containing fMLP-OMe analogue.

The synthesis and the biological activity of a pseudopeptide analogue of the chemotactic N-formyltripeptide fMLP-OMe, containing the azaTic (3,4-dihydro-2(1H)-phthalazinecarboxylic acid) residue replacing the native phenylalanine, is described. Whereas pseudopeptides containing linear alpha-azaamino acids are currently studied, data on the new group of analogues containing cyclic alpha-aza residues capable of limiting the rotameric distribution of the side chains (topological control) are just emerging in the literature. At our best knowledge, the here described [azaTic3]fMLP-OMe represents the first example of the introduction of this new type of alpha-aza residue into a natural bioactive peptide.

Carboxylic Acids↗

PubMed2003

Use of osmotic agents in microdialysis studies to improve the recovery of macromolecules.

The availability of microdialysis probes with higher molecular weight cutoff membranes has made it possible to measure larger molecular weight compounds like bioactive peptides and proteins. However, the higher molecular weight membrane cutoff allows for increased fluid loss from the probe, influencing both the physiology of the tissue compartment and analyte recovery. This study examined the ability of osmotic agents like bovine serum albumin (BSA) to offset the water loss from the microdialysis probe. In the presence of BSA, water loss from the microdialysis probe was minimized. Furthermore, addition of BSA to the perfusate produced significant increases in analyte recovery. Application of this technique to the measurement of bioactive macromolecules was examined using in vitro microdialysis of tumor necrosis factor (TNF) and interleukin-1 beta (IL-1B). The results of the present study suggest osmotic agents like BSA can prevent fluid loss from the microdialysis probe and improve analyte recovery.

Macromolecular Substances↗

PubMed1987

Acetylcholinesterase exhibits trypsin-like and metalloexopeptidase-like activity in cleaving a model peptide.

Acetylcholinesterase (EC 3.1.1.7) has been shown to possess an intrinsic peptidase activity. [Chubb et al. (1983), Neuroscience 10, 1369-1383]. To examine this activity further, the breakdown of a model hexapeptide (leu-trp-met-arg-phe-ala) LWMRFA was studied. Affinity-purified eel acetylcholinesterase rapidly cleaved the hexapeptide in a trypsin-like manner to produce two peptides (LWMR and FA). Acetylcholinesterase more slowly cleaved the C-terminal alanine residue from the peptide to yield LWMRF. Although the enzyme showed preference for cleaving the hexapeptide at its C-terminal, it was also able to cleave the N-terminal leucine residue form the tryptic product LWMR. Hydrolysis of the peptide at the tryptic site (arg4-phe5) was strongly inhibited by the trypsin inhibitor diisopropylfluorophosphate. Cleavage of the C-terminal alanine was only poorly inhibited by diisopropylfluorophosphate, but more strongly inhibited by metal-ion chelating agents, and it was increased in the presence of Zn2+ and Co2+. The pH optimum for cleavage at the tryptic site was 6, while that for the carboxypeptidase site was 8-9. These results show that acetylcholinesterase can hydrolyse peptides like a trypsin-like endopeptidase and a Zn2+- or Co2+-dependent exopeptidase, and they suggest that these two peptidase activities are associated with two separate active sites on the acetylcholinesterase molecule. As both peptidase activities eluted with acetylcholinesterase from a TSK 4000SW column when it was chromatographed by high-performance liquid chromatography, it is unlikely that the presence of either peptidase activity could be attributable to a contaminant in the acetylcholinesterase preparation. We suggest that acetylcholinesterase may be involved in the breakdown of bioactive peptides or their precursors in neuroendocrine cells.

Acetylcholinesterase↗

PubMed2001

Neutral endopeptidase is expressed on the follicular granulosa cells of rabbit ovaries.

Neutral endopeptidase (NEP) is a zinc metallopeptidase ubiquitously distributed in various tissues in mammals. This peptidase is involved in the post-secretory metabolism of various neuropeptides and peptide hormones in vivo, such as enkephalins, bradykinin, atrial natriuretic peptide, substance P and endothelins. In this paper we show that NEP is expressed in ovaries as a 110-kDa glycosylated integral membrane protein with enzymatic properties similar to those of the kidney protein. Using immunohistochemistry, we localize the peptidase in the granulosa cells of follicles at all stages of maturation, with the exception of atretic follicles. We also observe immunoreactive staining in the epithelia that lines the blood vessels in the medulla and the surface of the ovary. The co-localization of NEP and bioactive peptides known to be physiological substrates of NEP in other tissues suggests an important role for this protein in processes such as follicle maturation, ovulation, and/or regulation of ovarian blood flow, by modulating the physiological function of these peptides.

Animals↗

PubMed1998

Structure of cyclic peptides: the crystal and solution conformation of cyclo(Phe-Phe-Aib-Leu-Pro).

A solid-state and solution conformation analyses of the cyclopentapeptide cyclo(Phe-Phe-Aib-Leu-Pro) has been carried out by X-ray diffraction and nuclear magnetic resonance techniques. The structure of the hexagonal crystals, grown from a methanol solution [a = b = 16.530(4) A, c = 21.356(9) A, space group P6(5), Z = 6], shows the presence of one intramolecular N-H ..O=C hydrogen bond with the formation of a gamma-turn (C7). The Aib3 residue, at the center of the gamma-turn, presents unexpected values of the torsion angles [phi = 70.5 degrees and psi = -73.8 degrees], which have been observed only once before for this helicogenic residue. A cis peptide bond occurs between Leu4 and Pro5; all other peptide bonds are trans. The overall conformation for the cyclopentapeptide with one cis-peptide bond on one side and an intramolecular gamma-turn on the opposite side results in an equatorial topology of the side-chains of the Phe1, Phe2 and Leu4 residues. Indeed, the Calpha-Cbeta and Cbeta-Cgamma bonds of these residues lie approximately in the mean plane of the cyclic ring system. The structure is compared with data in the literature on cyclic pentapeptides. In addition the Pro-Phe-Phe moiety shows a conformation similar to that observed in other larger cyclic bioactive peptides, which indicates a reduced number of conformations for this sequence. The solution study was carried out in three different solvent systems: chloroform, acetonitrile and methanol in the temperature interval 220-300 K. In all three solvents the room temperature spectra show that the peptide is conformationally nonhomogeneous. In acetonitrile at low temperatures it is possible to reduce the conformational equilibrium to two predominant conformers which differ for the cis-trans isomerism of the Leu4-Pro5 peptide bond.

Magnetic Resonance Spectroscopy↗

PubMed1997

Effects of hydrogen and bicarbonate ions on endocrine cells in fetal rat lung organ cultures.

Concentrations of H+ and HCO3- rise in fluid lining hypercapnic airways. Effects of these ions on pulmonary endocrine cells were studied in 119 fetal rat lung organ cultures by semiquantitative staining for calcitonin gene-related peptide (CGRP)-like immunoreactive material. Intracellular CGRP was determined in cultures under "no-release" baseline conditions and after incubation in control or test media. After exposure to HCO3(-)-free medium at pH 7.4 (incubation control), CGRP fell moderately from no-release levels. Bombesin (1 ng/ml) promoted further significant loss of peptide, which was dependent on extracellular Ca2+ and inhibited by somatostatin and [D-Arg(1),D-Pro(2),D-Trp(7,9),Leu(11)]substance P, a bombesin receptor antagonist. CGRP staining of explants incubated with 24 mM HCO3- maintained no-release levels at and above pH 7.1 but decreased significantly at pH 6.8. The drop was blocked by somatostatin or exclusion of HCO3- and was not augmented by bombesin or 48 mM HCO3-. Results suggest that pulmonary endocrine cells may respond to hypercapnia by releasing bioactive peptides like CGRP, thus stimulating afferent nerves and altering patterns of ventilation and perfusion.

Animals↗

PubMed2005

Agouti-related protein: more than a melanocortin-4 receptor antagonist?

It is well established that agouti-related protein (AGRP) can act as a competitive antagonist to proopiomelanocortin (POMC)-derived peptides at the melanocortin-4 receptor (MC4R), and that this homeostatic mechanism is important as a means of coordinating appetite with perceived metabolic requirement. However, there are clearly additional facets to the physiological role of AGRP, given that it is active in MC4R knockout mice and it has strikingly long-lasting effects on food intake, compared with MC4R agonists. In this review we focus on: (i) evidence that AGRP is more sensitive to perturbations in energy balance than POMC and is therefore the primary basis of melanocortinergic regulation. (ii) Evidence that the bioactive peptide AGRP83-132, acts by alternate mechanism(s) to elicit its long-term effects on food intake. (iii) Evidence that AGRP is post-translationally cleaved to generate AGRP83-132 and one or more N terminal peptides, which may have an important physiological role(s) that are independent of the melanocortin system. A clear understanding of how proAGRP processing is regulated, and the role of resultant peptides, may define additional therapeutic targets in the treatment of obesity.

Agouti-Related Protein↗

PubMed1997

The action of Taiwan cobra venom on methionine enkephalin: a useful assay for oligopeptidase content.

The pentapeptide methionine enkephalin is readily hydrolysed by the oligopeptidase activity contained in Taiwan cobra (Naja naja atra) venom. It is a significantly better substrate than the peptides previously used to identify the presence of this enzyme, but it retains many of the sequence characteristics shared by these other peptides. Analysis of the manner of hydrolysis by means of high-performance liquid chromatography and electrospray mass spectrometry revealed the simultaneous actions of at least two types of oligopeptidase on the neuropeptide, producing two routes of initial breakdown. By one route, an endopeptidase cleaved the Gly-Phe bond of enkephalin first to release Tyr-Gly-Gly and Phe-Met. By the other route, an aminopeptidase was able to release Tyr and Gly-Gly-Phe-Met by cleaving the Tyr-Gly bond first. From amongst the various peptide fragments produced, Tyr-Gly-Gly was subject to immediate aminopeptidase action to release Tyr and Gly-Gly. The free Tyr produced in these reactions was in turn quickly transformed by the L-amino acid oxidase in the venom. The kinetic qualities of the enkephalin hydrolysis, and the conversions of the fragments Tyr-Gly-Gly and Tyr, were measured. Methionine enkephalin has potential as a routine assay for venom oligopeptidases, either in testing the venoms from other species or in attempts to purify these enzymes. Moreover, the ease of hydrolysis of this bioactive peptide, coupled with the revelation of the other enzymic steps involving the fragments generated, may provide important clues as to the possible role of the oligopeptidases (and L-amino acid oxidase) in the venom.

Amino Acid Oxidoreductases↗

PubMed1998

A proposed bioactive conformation of peptide T.

The conformational profiles of Peptide T, (5-8)Peptide T, [Abu5](4-8)Peptide T and (4-8)Peptide T were computed independently to assess the geometrical characteristics of the bioactive conformation of Peptide T. The conformational profiles of the peptides were computed within the molecular mechanics framework using an effective dielectric constant of 80. The conformational space was thoroughly sampled using an iterative simulated annealing protocol. The bioactive conformation was assessed by pairwise cross comparisons of each of the unique low energy conformations found for each of the different analogs studied. After a putative bioactive conformation was selected, in order to further validate our hypothesis the conformational profile of the potent compound cyclo(Thr-Thr-Asn-Tyr-Thr-Asp) was computed and the putative bioactive conformation was found. The conformation exhibits a pseudo beta-turn involving the side chain of Thr5 and the carbonyl oxygen of Tyr7 forming a C12 ring.

Amino Acid Sequence↗

PubMed2002

Chemo-enzymatic synthesis of the glycosylated alpha-mating factor of Saccharomyces cerevisiae and analysis of its biological activity.

The effect of glycosylation on a bioactive peptide was studied using yeast Saccharomyces cerevisiae alpha-mating factor, which is composed of 13 amino acids. In this study, we prepared glycosylated alpha-mating factor by chemo-enzymatic synthesis. At first, N-acetylglucosaminyl alpha-mating factor (Trp-His-Trp-Leu-Gln(GlcNAc)-Leu-Lys-Pro-Gly-Gln-Pro-Met-Tyr) was chemically synthesized by the solid-phase method. Then, using the transglycosylation activity of Mucor hiemalis endo-beta-N-acetylglucosaminidase, we synthesized glycosylated alpha-mating factor with a glutamine-linked sialo complex type oligosaccharide. The biological activity of alpha-mating factor derivatives was examined by means of a growth arrest assay using secreted-protease-defective a cells of S. cerevisiae. The results showed that the bioactivity of glycosylated alpha-mating factor was lower than that of native alpha-mating factor. However, when sialic acid was removed from the complex type sugar chain of glycosylated alpha-mating factor, its bioactivity was recovered. Glycosylated alpha-mating factor exhibited higher resistance against proteolysis than native alpha-mating factor. It was found that the bioactivity of N-acetylglucosaminyl alpha-mating factor was higher than that of alpha-mating factor. Circular dichroism studies indicated that a slight change in the structure of alpha-mating factor may influence its activity.

Acetylglucosamine↗

PubMed1996

Annetocin, an annelid oxytocin-related peptide, induces egg-laying behavior in the earthworm, Eisenia foetida.

Annetocin, an oxytocin-related peptide which we isolated from the earthworm Eisenia foetida, induced a series of egg-laying-related behaviors in the earthworms. These stereotyped behaviors consisted of well-defined rotatory movements, characteristic body-shape changes, and mucous secretion from the clitellum. Each of these behaviors is known to be associated with formation of the cocoon in which eggs are deposited. In fact, some of the earthworms injected with annetocin (> 5 nmol) laid eggs. Such egg-laying-related behaviors except for oviposition were also induced by oxytocin, but not by Arg-vasopressin and some other bioactive peptides isolated from E. foetida. Furthermore, annetocin also induced these egg-laying-like behaviors in the leech Whitmania pigra, but not in the polychaete Perinereis vancaurica. These results suggest that annetocin plays some key role in triggering stereotyped egg-laying behaviors in terrestrial or fresh-water annelids that have the clitella.

Amino Acid Sequence↗

PubMed1999

Synthesis, conformational study, and spectroscopic characterization of the cyclic C alpha, alpha-disubstituted glycine 9-amino-9-fluorenecarboxylic acid.

A series of terminally blocked peptides (to the pentamer level) from L-Ala and the cyclic C alpha, alpha-disubstituted Gly residue Afc and one Gly/Afc dipeptide have been synthesized by solution method and fully characterized. The molecular structure of the amino acid derivative Boc-Afc-OMe and the dipeptide Boc-Afc-Gly-OMe were determined in the crystal state by X-ray diffraction. In addition, the preferred conformation of all of the model peptides was assessed in deuterochloroform solution by FT-IR absorption and 1H-NMR. The experimental data favour the conclusion that the Afc residue tends to adopt either the fully-extended (C5) or a folded/helical structure. In particular, the former conformation is highly populated in solution and is also that found in the crystal state in the two compounds investigated. A comparison with the structural propensities of the strictly related C alpha, alpha-disubstituted Gly residues Ac5c and D phi g is made and the implications for the use of the Afc residue in conformationally constrained analogues of bioactive peptides are briefly examined. A spectroscopic (UV absorption, fluorescence, CD) characterization of this novel aromatic C alpha, alpha-disubstituted Gly residue is also reported.

Amino Acids↗

PubMed2004

Crystal structure of human dipeptidyl peptidase IV in complex with a decapeptide reveals details on substrate specificity and tetrahedral intermediate formation.

Dipeptidyl peptidase IV (DPPIV) is a member of the prolyl oligopeptidase family of serine proteases. DPPIV removes dipeptides from the N terminus of substrates, including many chemokines, neuropeptides, and peptide hormones. Specific inhibition of DPPIV is being investigated in human trials for the treatment of type II diabetes. To understand better the molecular determinants that underlie enzyme catalysis and substrate specificity, we report the crystal structures of DPPIV in the free form and in complex with the first 10 residues of the physiological substrate, Neuropeptide Y (residues 1-10; tNPY). The crystal structure of the free form of the enzyme reveals two potential channels through which substrates could access the active site-a so-called propeller opening, and side opening. The crystal structure of the DPPIV/tNPY complex suggests that bioactive peptides utilize the side opening unique to DPPIV to access the active site. Other structural features in the active site such as the presence of a Glu motif, a well-defined hydrophobic S1 subsite, and minimal long-range interactions explain the substrate recognition and binding properties of DPPIV. Moreover, in the DPPIV/tNPY complex structure, the peptide is not cleaved but trapped in a tetrahedral intermediate that occurs during catalysis. Conformational changes of S630 and H740 between DPPIV in its free form and in complex with tNPY were observed and contribute to the stabilization of the tetrahedral intermediate. Our results facilitate the design of potent, selective small molecule inhibitors of DPPIV that may yield compounds for the development of novel drugs to treat type II diabetes.

Animals↗

PubMed2002

Electrochromatography in microchips: reversed-phase separation of peptides and amino acids using photopatterned rigid polymer monoliths.

A microfabricated glass chip containing fluidic channels filled with polymer monolith has been developed for reversed-phase electrochromatography. Acrylate-based porous polymer monoliths were cast in the channels by photopolymerization to serve as a robust and uniform stationary phase. UV light-initiated polymerization allows for patterning of polymer stationary phase in the microchip, analogous to photolithography, using a mask and a UV lamp for optimal design of injection, separation, and detection manifolds. The monoliths are cast in situ in less than 10 min, are very reproducible with respect to separation characteristics, and allow easy manipulation of separation parameters such as charge, hydrophobicity, and pore size. Moreover, the solvent used to cast the polymer enables electroosmotic flow, allowing the separation channel to be conditioned without need for high-pressure pumps. The microchip was used for separation of bioactive peptides and amino acids labeled with a fluorogenic dye (naphthalene-2,3-dicarboxaldehyde) followed by laser-induced fluorescence detection using a Kr+ ion laser. The microchip-based separations were fast (six peptides in 45 s), efficient (up to 600,000 plates/m), and outperformed the capillary-based separations in both speed and efficiency. We have also developed a method for complete removal of polymer from the channels by thermal incineration to regenerate the glass chips.

Amino Acids↗

PubMed2006

Identification of bikunin as an endogenous inhibitor of dynorphin convertase in human cerebrospinal fluid.

Dynorphin-converting enzymes constitute a group of peptidases capable of converting dynorphins to enkephalins. Through the action of these enzymes, the dynorphin-related peptides bind to delta-opioid instead of kappa-opioid receptors, leading to a change in the biological function of the neuropeptides. In this article, we describe the identification of the protein bikunin as an endogenous, competitive inhibitor of a dynorphin-converting enzyme in human cerebrospinal fluid. This protein is present together with its target enzyme in the same body fluids. The K(M) value of the convertase was found to be 9 microm, and the K(i) value of the inhibitor was 1.7 nm. The finding indicates that bikunin may play a significant role as a regulatory mechanism of neuropeptides, where one bioactive peptide is converted to a shorter sequence, which in turn, can affect the action of its longer form.

Alpha-Globulins↗

PubMed2004

Role of aminopeptidases in the blood pressure regulation.

In addition to the neural and autoregulatory factors, blood pressure (BP) is regulated by humoral factors including vasoactive peptides. When evaluating the peptide actions, degradation by proteases should be also considered in addition to the generation of peptides and their receptors. This review describes the roles of aminopeptidase A, placental leucine aminopeptidase and kininase I, which are enzymes responsible for hydrolyzing angiotensin II (AngII), vasopressin (AVP) and bradykinin (BK), respectively, in BP regulation. Especially, we focus on the association of the proteases with preeclampsia, hypertensive disorder peculiar to pregnancy, since one of the representative organs that are rich in theses proteases is placenta. Although the physiological roles of the placental proteases have not been fully understood, several lines of evidence suggest that the proteases are involved in the maintenance of pregnancy homeostasis including fetal and maternal BP regulation through the metabolism of bioactive peptides at the interface between mother and fetus.

Amino Acid Sequence↗