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PubMed1995

A new Myxococcus xanthus gene cluster for the biosynthesis of the antibiotic saframycin Mx1 encoding a peptide synthetase.

The gene cluster for the biosynthesis of the heterocyclic quinone antibiotic saframycin Mx1 of Myxococcus xanthus DM504/15 was inactivated and tagged by Tn5 insertions. The tagged genes were cloned in Escherichia coli and used to select overlapping cosmid clones spanning 58 kb of the M. xanthus genome. Gene disruption experiments defined a > or = 18 kb contiguous DNA region involved in saframycin biosynthesis. Sequencing of part of this region revealed a large ORF containing two 600-amino-acid domains with similarity to peptide synthetase amino-acid-activating sequences, suggesting that saframycin Mx1 is synthesized by a nonribosomal multienzyme complex, similar to other bioactive peptides.

Amino Acid Sequence↗

PubMed1994

Pituitary adenylate cyclase-activating polypeptide regulation of AtT-20/D16v corticotrope cell proopiomelanocortin expression and secretion.

The hypothalamic peptides pituitary adenylate cyclase-activating polypeptides (PACAPs) may play central roles in the regulation of anterior pituitary gland function. The two pro-PACAP-derived peptides, PACAP38 and PACAP27, are posttranslationally processed from a common precursor molecule and share amino acid sequence homology with vasoactive intestinal peptide (VIP). To further evaluate and compare the physiological roles of these peptides, we have examined the short and long term effects of PACAP38, PACAP27, and VIP on POMC-related peptide production in the mouse AtT-20/D16v corticotrope cell line. Short term (0.5- to 5-h) treatment of AtT-20/D16v cells with PACAP38, PACAP27, or VIP elicited similar concentration-dependent and biphasic stimulation of ACTH release. Half-maximal stimulation of the higher potency phase was attained with 1-2 nM peptide; maximal secretion was observed at peptide concentrations greater than 100 nM. Similar 2- to 3-fold maximal stimulation of ACTH secretion was elicited by all three bioactive peptides; linear sustained ACTH secretion was observed. Long term (12- to 72-h) treatment of AtT-20/D16v cultures with these peptides resulted in substantially decreased rates of cellular division, with a concomitant increase in cell size and formation of cell processes characteristic of cellular differentiation. These morphological changes coincided with a sustained 2-fold increase in AtT-20 corticotrope intracellular hormone content and secretion. Northern blot analysis demonstrated a parallel induction of POMC mRNA expression by the PACAP38, PACAP27, and VIP peptides. These results suggest that AtT-20/D16v cells possess primarily the type II PACAP receptor subtype, which binds PACAP38, PACAP27, and VIP with apparent equal affinity. Furthermore, the long term effects of these peptides implicate a potentially significant role for PACAP and VIP peptides in the mediation of altered pituitary gland functions. In this vein, the PACAPs may prove to be unique regulators of neuroendocrine function and development.

Animals↗

PubMed2002

Inhibition of proteolysis in luminal extracts from the intestine of the brushtail possum.

The proteolytic activity of luminal extracts from five regions (duodenum, jejunum, ileum, caecum and colon) of the brushtail possum intestine towards bovine serum albumin (BSA) and human luteinizing hormone releasing hormone (LHRH) was investigated. There were no significant differences in degradation rates between fresh and previously frozen extracts from any region of the possum intestine. The inhibition of degradation of BSA by luminal extracts from two regions (jejunum and ileum) and of LHRH from four regions (jejunum, ileum, caecum and colon) was evaluated. Soybean trypsin-chymotrypsin inhibitor (SBTI), sodium deoxycholate, Carbopol 934P, bacitracin and bestatin significantly inhibited the degradation of both LHRH and BSA (P < 0.05). SBTI almost totally inhibited the proteolysis of BSA and the peptidolysis of LHRH in extracts from the small intestine. This finding suggests that serine proteases such as chymotrypsin are responsible for the protein and peptide degradation in luminal extracts. It is concluded that including serine protease inhibitors in a formulation may enhance oral delivery of bioactive peptides and proteins to possums.

Animals↗

PubMed2001

Biosynthesis and secretion of adrenomedullin and proadrenomedullin N-terminal 20 peptide in a rat model of endotoxin shock.

To study the biosyntheses and pathophysiological roles of adrenomedullin (AM) and proadrenomedullin N-terminal 20 peptide (PAMP) in septic shock, we compared the time course of plasma concentrations of these peptides and blood pressure in rats injected with either 0.9% saline (control group) or lipopolysaccharide (LPS group). The plasma AM concentration in the LPS group did not increase 30 and 60 min after LPS injection, at which time points the blood pressure remained low. Thereafter, AM rapidly increased, and it amounted to 35 times the basal value 4 h after injection, when the blood pressure returned to the basal level. The increment of plasma PAMP in the LPS group was lower than that of AM. We also examined the tissue concentration of AM and PAMP--as well as the tissue expression of proadrenomedullin (proAM) mRNA--in the LPS and control groups. LPS significantly increased the tissue concentrations of AM and PAMP in the lung, but decreased them in the adrenal gland and cardiac atrium. The LPS injection augmented proAM gene transcription in the lung, adrenal gland and aorta. In an immunohistochemical examination, AM staining was intense in alveolar endothelial cells of the lung in the LPS group. Thus, this septic shock model had high plasma levels of PAMP as well as AM, while the biosynthesis and secretion of the two peptides may have been differentially regulated in various tissues of rats injected with LPS. The present results suggest that these two bioactive peptides may play different roles in the pathophysiology of septic shock.

Adrenomedullin↗

PubMed2003

Rapid assay to detect possible natural substrates of proteases in living cells.

Proteolysis is a regulatory step in many physiological processes, but which proteases in what cellular sites are involved in activation or degradation of which peptides is not well known. We developed a rapid assay consisting of living cells and fluorogenic protease substrates to determine which bioactive peptides are possible natural substrates of a specific protease with the multifunctional or moonlighting protein CD26/dipeptidyl peptidase IV (DPPIV) as a model. CD26/DPPIV catalyzes cleavage of peptides from the amino terminus of peptides with proline at the penultimate position. Many biologically active peptides, such as beta-casomorphin1-5, contain proline in the penultimate position. We incubated living Jurkat cells, which are T cells that lack CD26/DPPIV, and CD26/DPPIV-transfected Jurkat cells in the presence of the fluorogenic substrate [Ala-Pro]2-cresyl violet (Magic Red) and beta-casomorphin1-5. Fluorescent cresyl violet was generated by CD26/DPPIV-transfected Jurkat cells but not by wild-type Jurkat cells with a Km of 3.7 microM. beta-Casomorphin1-5 appeared to be a possible natural substrate of CD26/DPPIV, because it inhibited production of fluorescence competitively (Ki = 60 microM). The assay using living cells and a fluorogenic protease substrate is an efficient system to determine whether specific peptides are possible natural substrates of a particular protease.

Biological Assay↗

PubMed1993

High-performance liquid chromatography of amino acids, peptides, and proteins. 123. Dynamics of peptides in reversed-phase high-performance liquid chromatography.

The dynamics of several peptides in reversed-phase high-performance liquid chromatography (RP-HPLC) have been investigated on both n-octadecyl (C18) silica and n-butyl (C4) silica sorbents. In particular, the conformational interconversions and the relative rates of chromatographic relaxation of bombesin, glucagon, and beta-endorphin on both C18 and C4 n-alkylsilicas were monitored by examining changes in the experimental bandwidths of these peptides as a function of temperature and column residence time under linear gradient elution RP-HPLC conditions. The observed band-broadening trends were correlated with previously derived retention parameters and thermodynamic descriptors of the association process determined for bombesin, beta-endorphin, glucagon, and a control peptide, penta-L-phenylalanine. This study confirms that bandwidth measurements can be used as an integral experimental component to study the effect of the secondary structure of peptidic solutes on their RP-HPLC retention behavior. Further, the data demonstrate the utility of RP-HPLC as a tool to examine peptide conformational dynamics at hydrophobic surfaces. The relevance of these results to the general phenomenon of peptide-lipid interactions is discussed in terms of the associated evidence for lipid-induced changes in the conformation of these three bioactive peptides.

Amino Acid Sequence↗

PubMed2006

Antimicrobial peptides activate the Vibrio cholerae sigmaE regulon through an OmpU-dependent signalling pathway.

Vibrio cholerae, an enteric pathogen, is subject to assault by several membrane-acting, host gut-derived antimicrobial peptides (AP). We previously found that a major V. cholerae outer membrane protein, OmpU, confers resistance to polymyxin B and to a bioactive peptide (P2) derived from the human bactericidal/permeability-increasing protein. Here, we report that the alternative sigma factor sigma(E) also plays a critical role in determining V. cholerae resistance to AP and that OmpU and sigma(E) lie in the same pathway. In fact, we found that OmpU is a key determinant of basal sigma(E) expression. We also found that sublethal AP exposure activates sigma(E) and the sigma(E)-mediated periplasmic stress response. sigma(E) is not activated by P2 in V. cholerae cells lacking OmpU or DegS, a periplasmic protease that controls sigma(E) activity. The lack of AP-elicited sigma(E) activation in a strain harbouring a point mutation in OmpU's putative DegS-binding residues provides support for a link between OmpU and DegS-mediated activation of sigma(E). We propose that AP-induced membrane perturbations change the conformation of OmpU to trigger a DegS-dependent sigma(E)-activating cascade. Thus, OmpU appears to act as a sensor component in a signal transduction pathway.

Adhesins, Bacterial↗

PubMed1993

Thimet oligopeptidase--a review of a thiol dependent metallo-endopeptidase also known as Pz-peptidase endopeptidase 24.15 and endo-oligopeptidase.

Thimet oligopeptidase (EC 3.4.24.15) is a thiol-dependent metallo-endopeptidase also known as Pz-peptidase, collagenase-like peptidase, endooligopeptidase A, soluble metallo-endopeptidase and endopeptidase 24.15. The enzyme is closely related to the yeast proteinase yscD. Thimet oligopeptidase (M(r) 74000) is widely distributed in animals and plants. In rat liver it exists in a cytoplasmic and mitochondrial form; a membrane-bound form of the enzyme was discovered in rat brain. Thimet oligopeptidase hydrolyses small peptides but does not act on proteins. In rat brain thimet oligopeptidase is involved in the generation of enkephalins and inactivation of bioactive peptides and experiments with yeast provided good evidence that the enzyme is involved in the late stages of cytoplasmatic protein degradation.

Amino Acid Sequence↗

PubMed2002

Molecular characterization of frog chromogranin B reveals conservation of selective sequences encoding potential novel regulatory peptides.

Chromogranin B (CgB) is a member of the granin family of neuroendocrine secretory proteins, which has been proposed to play a role in secretory granule biogenesis and as a precursor to bioactive peptides. The cloning of CgB in a phylogenetically distant vertebrate, the frog Rana ridibunda, reveals a modest overall homology (35-40%) with mammalian CgB. However, the sequences of the N- and C-terminal regions are more highly conserved (57-65% amino acid identity) and may give rise to novel regulatory peptides. In frog, intense expression of CgB mRNA was observed in particular structures of the brain and in the distal lobe of the pituitary.

Amino Acid Sequence↗

PubMed2001

Calpha methylation in molecular recognition. Application to substance P and the two neurokinin-1 receptor binding sites.

Two binding sites NK-1M (major, more abundant) and NK-1m (minor) are associated with the neurokinin-1 receptor. For the first time with a bioactive peptide, the Calpha methylation constraint, shown to be a helix stabiliser in model peptides, was systematically used to probe the molecular requirements of NK-1M and NK-1m binding sites and the previously postulated bioactive helical conformation of substance P (SP). Seven Calpha methylated analogues of the undecapeptide SP (from position 5-11) have been assayed for their affinities and their potencies to stimulate second messenger production. The consequences of Calpha methylation on the structure of SP have been analysed by circular dichroism and nuclear magnetic resonance combined with restrained molecular dynamics. The decreased potencies of six out of these seven Calpha methylated SP analogues do not allow the identification of any clear-cut differences in the structural requirements between the two binding sites. Strikingly, the most active analogue, [alphaMeMet5]SP, leads to variable subnanomolar affinity and potency when interacting with the NK-1m binding site. The conformational analyses show that the structural consequences associated with Calpha methylation of SP are sequence dependent. Moreover, a single Calpha methylation is not sufficient by itself to drastically stabilize a helical structure even pre-existing in solution, except when Gly9 is substituted by an alpha-aminoisobutyric acid. Furthermore, Calpha methylation of residues 5 and 6 of SP in the middle of the postulated helix does not stabilize, but decreases (to different extents) the stability of the helical structure previously observed in the 4-8 domain of other potent SP analogues.

Animals↗

PubMed2003

Synthesis and characterization of a macrocyclic near-infrared optical scaffold.

Macrocyclization of a bioactive peptide with a bifunctional near-infrared fluorescent optical probe gives a compound that retained the receptor binding affinity of the peptide and the photophysical properties of the optical probe. The robust nature of the new compound provides a structural framework for optimizing the activity of bioactive molecules and for monitoring chemical or biological processes in vivo and in vitro by near-infrared optical methods.

Cyclization↗

PubMed2000

Kassinatuerin-1: a peptide with broad-spectrum antimicrobial activity isolated from the skin of the hyperoliid frog, Kassina senegalensis.

Kassinatuerin-1 (GFMKYIGPLI(10)PHAVKAISDL(20)I.NH(2)) was isolated in high yield (75 nmol/g) from an extract of the skin of a Hyperoliid frog, the African running frog Kassina senegalensis and its sequence was confirmed by total synthesis. The peptide inhibited growth of the gram-negative bacterium Escherichia coli (minimum inhibitory concentration, MIC = 4 microM), the gram-positive bacterium Staphylococcus aureus (MIC = 8 microM), and the yeast Candida albicans (MIC = 70 microM). A structurally related peptide, kassinatuerin-2 (FIQYLAPLI(10)PHAVKAISDL(20)I.NH(2)) was also isolated in high yield (96 nmol/g) from the extract but was devoid of antimicrobial activity against these microrganisms. Kassinatuerin-1 may be classified with other linear, cationic antimicrobial peptides that can potentially adopt an amphipathic alpha-helical conformation but it contains almost no amino acid sequence identity with previously characterized bioactive peptides from frog skin.

Amino Acid Sequence↗

PubMed1998

Empirical modifications to the Amber/OPLS potential for predicting the solution conformations of cyclic peptides by vacuum calculations.

BACKGROUND: Peptides have ubiquitous roles in all biological systems and are thus of interest in both basic and applied research. The rational design of bioactive peptides could be greatly enhanced by an efficient method for accurately predicting the conformations that these molecules can adopt in solution. As a design process inevitably requires testing numerous molecules, an efficient method would require the calculations to be performed in vacuum. RESULTS: Attempts to predict the conformations of cyclic peptides using a simulated annealing protocol with the Amber/OPLS potential in vacuum resulted, not unexpectedly, in overly packed, non-native conformations. We therefore empirically modified the potential by several cycles of structure prediction and function refinement until a good fit between experimental and predicted conformations was obtained. Three major modifications to the potential were required in order to reproduce the solution structures of cyclic peptides: explicit torsional energies for the peptide backbone torsional angles; explicit hydrogen-bonding energies for backbone hydrogen bonds; and a penalty for close approaches between uncharged and charged atoms. CONCLUSIONS: Using the modified potential, we predicted the solution conformations of cyclic peptides in the size range of 5-10 residues with reasonable accuracy.

Amino Acid Sequence↗

PubMed1992

Conformational analysis of an opioid peptide in solvent media that mimic cytoplasm viscosity.

Many neuropeptides exert their action between the presynaptic vesicles and postsynaptic transmembrane receptors, crossing different layers of specialized cytoplasm. Biomimetic media usually employed to study bioactive peptides do not reproduce the physico chemical environment of cytoplasm--in particular, the high viscosity of this biological fluid. Here we describe a conformational study of a delta-selective opioid peptide, deltorphin I, at variable temperatures in several biocompatible media characterized by varying values of viscosity and dielectric constant. It was found that only viscosity, among these parameters, induces ordered conformations; that is, it acts as a conformational sieve. This finding suggests that the high viscosity of the intersynaptic fluid contributes, in addition to the membrane catalysis proposed by Schwyzer, in overcoming the so-called entropic barrier to the transition state of peptide-receptor interaction by selecting ordered conformations prior to receptor interaction. The folded conformer found in the 80:20 (v:v) DMSOd6/H2O cryoprotective mixture at 265 K has a shape consistent with those of rigid nonpeptidic opiates.

Amino Acid Sequence↗

PubMed2003

Bioactivity of a peptide derived from acetylcholinesterase in hippocampal organotypic cultures.

While the molecular basis underlying the non-classical actions of acetylcholinesterase (AChE) is presently unknown, a candidate peptide sequence located at the C-terminus of AChE (AChE-peptide) has recently been identified. This study explored the bioactivity of synthetic AChE-peptide using in vitro organotypic cultures of rat hippocampus. Neurotrophic effects, detected as increased neurite outgrowth from MAP-immunopositive neurones, were apparent using 1 h exposure to 1-10 nM AChE-peptide. As exposure time increased, cell death occurred as indicated by TdT-mediated dUTP biotin nick-end labelling (TUNEL). This process was accelerated at higher AChE-peptide concentrations, with lactate dehydrogenase (LDH) efflux observed following prolonged exposure to 1-10 microM AChE-peptide. Apoptotic cells were detected by Hoechst 33342 staining following 24 h application of 10 nM AChE-peptide. However, propidium iodide reactivity revealed a simultaneous loss of membrane integrity indicative of necrosis, suggesting that AChE-peptide induces cell death via a continuum of apoptotic and necrotic processes. Prolonged exposure to AChE-peptide also resulted in a concentration-dependent reduction in neurite outgrowth from MAP2-positive neurons, although immunohistochemical studies provided some evidence of differential responsiveness in GABAergic, cholinergic and somatostatin neurones. In addition, bioactivity was sequence specific since a scrambled AChE-peptide analogue, as well as the corresponding BuChE-peptide, was ineffective. In conclusion, the bioactivity associated with the AChE-peptide sequence may account for the non-cholinergic actions of AChE, whilst its neurotrophic-apoptotic-necrotic spectrum of action may be involved in the aetiology of neurodegenerative disorders such as Alzheimer's disease.

Acetylcholinesterase↗

PubMed2004

In vitro assessment of bioactive coatings for neural implant applications.

Recent efforts in our laboratory have focused on developing methods for immobilizing bioactive peptides to low cell-adhesive dextran monolayer coatings and promoting biospecific cell adhesion for biomaterial implant applications. In the current study, this dextran-based bioactive coating technology was developed for silicon, polyimide, and gold, the base materials utilized to fabricate our prototype neural implants. Chemical composition of all modified surfaces was verified by X-ray photoelectron spectroscopy (XPS). We observed that surface-immobilized dextran supported very little cell adhesion in vitro (24-h incubation with serum-supplemented medium) on all base materials. Inactive nonadhesion-promoting Gly-Arg-Ala-Asp-Ser-Pro peptides immobilized on dextran-coated materials promoted adhesion and spreading at low levels not significantly different from dextran-coated substrates. Arg-Gly-Asp (RGD) peptide-grafted surfaces were observed to promote substantial fibroblast and glial cell adhesion with minimal PC12 (neuronal cell) adhesion. In contrast, dextran-coated materials with surface-grafted laminin-based, neurite-promoting Ile-Lys-Val-Ala-Val (IKVAV) peptide promoted substantial neuron cell adhesion and minimal fibroblast and glial cell adhesion. It was concluded that neuron-selective substrates are feasible using dextran-based surface chemistry strategies. The chemical surface modifications could be utilized to establish a stable neural tissue-implant interface for long-term performance of neural prosthetic devices.

Amino Acid Sequence↗

PubMed1987

The enkephalin-containing cell: strategies for polypeptide synthesis and secretion throughout the neuroendocrine system.

1. Enkephalinergic cells are found throughout the diffuse neuroendocrine system, in the adrenal medulla, brain, spinal cord, peripheral and enteric nervous systems, and endocrine pancreas. 2. In each of these diverse cell types, the enkephalin phenotype is (i) established during development, (ii) modified by the particular environment in which the cell is located, and (iii) maintained by ongoing biosynthesis at a rate consistent with loss of enkephalins from the cell during periods of secretion. 3. Enkephalin expression and biosynthesis have been studied in several neuroendocrine cell types and tumor cell lines. Transcriptional, translational, and posttranslational factors can play a role at all three stages (establishment, modification, and maintenance) in the regulation of enkephalin expression during the lifetime of the cell. 4. Cyclic nucleotides, glucocorticoids, and calcium may all act to control the overall level of enkephalin biosynthesis pretranslationally, while regulation of posttranslational processing of proenkephalin seems to be important in determining the pattern of proenkephalin-derived opiate peptides produced in a given tissue. 5. The themes (and variations) of cell regulation that apply to enkephalin expression may be similar for other bioactive peptides produced in neural and endocrine tissues.

Animals↗

PubMed2004

Site-specific microinjection of liposomes into the brain for local infusion of a short-lived peptide.

The short-lived peptide, angiotensin-(1-7) (Ang-(1-7)), was encapsulated in different liposome preparations, in order to evaluate the influence of membrane fluidity, membrane surface, liposome size and dose of peptide on the cardiovascular effects of the encapsulated peptide at a specific site of the brain. These preparations were microinjected unilaterally into the rostral ventrolateral medulla (RVLM) of Wistar rats, and mean arterial blood pressure (MAP) and heart rate (HR) were registered by telemetry. Pegylated, rigid and calibrated (200 nm) liposomes, containing 50 ng of Ang-(1-7), elicited a significant increase of MAP for at least 7 days, in contrast to empty liposomes or non-pegylated liposomes. When a two-fold higher peptide dose was employed or when pegylated liposomes were used in the fluid state or uncalibrated, less pronounced pressor effects were observed. These data show that the cardiovascular responses to the microinjection of Ang-(1-7)-containing liposomes into the RVLM can be modulated through the manipulation of liposome characteristics. These results can be explained by the influence of liposome characteristics on the flux of peptide release. It is expected that this new method will encounter numerous applications in the study of the chronic actions of short-lived bioactive peptides in specific sites of the brain.

Angiotensin I↗