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PubMed1998

Novel galanin receptor ligands.

Galanin is a neuroendocrine peptide which is 29/30 amino acids in length and is recognised by G-protein-coupled central nervous system receptors via its N-terminus. We synthesised several galanin receptor ligands and fragments around C-terminal extensions of galanin(1-13) to yield chimeric peptides with C-terminals corresponding to bioactive peptides like bradykinin(2-9), mastoparan, neuropeptide Y(25-36) or substance P(5-11), respectively. We also synthesised short galanin analogs in which galanin(1-13) was C-terminally elongated with Lys14; different pharmacologically active small molecules were then attached to the epsilon-amino group of Lys14. Several cysteine-substituted linear and ring closed analogs of galanin(1-9) and galanin(1-16) were also synthesised. The equilibrium binding constants for these peptides at hypothalamic galanin receptors were determined and found in the subnanomolar to micromolar range. The large number of peptides and their binding affinities presented here permit structure-activity relationship analysis of peptide-type ligands to galanin receptors.

Amino Acid Sequence↗

PubMed2000

Towards understanding the kallikrein-kinin system: insights from measurement of kinin peptides.

The kallikrein-kinin system is complex, with several bioactive peptides that are formed in many different compartments. Kinin peptides are implicated in many physiological and pathological processes including the regulation of blood pressure and sodium homeostasis, inflammatory processes, and the cardioprotective effects of preconditioning. We established a methodology for the measurement of individual kinin peptides in order to study the function of the kallikrein-kinin system. The levels of kinin peptides in tissues were higher than in blood, confirming the primary tissue localization of the kallikrein-kinin system. Moreover, the separate measurement of bradykinin and kallidin peptides in man demonstrated the differential regulation of the plasma and tissue kallikrein-kinin systems, respectively. Kinin peptide levels were increased in the heart of rats with myocardial infarction, in tissues of diabetic and spontaneously hypertensive rats, and in urine of patients with interstitial cystitis, suggesting a role for kinin peptides in the pathogenesis of these conditions. By contrast, blood levels of kallidin, but not bradykinin, peptides were suppressed in patients with severe cardiac failure, suggesting that the activity of the tissue kallikrein-kinin system may be suppressed in this condition. Both angiotensin converting enzyme (ACE) and neutral endopeptidase (NEP) inhibitors increased bradykinin peptide levels. ACE and NEP inhibitors had different effects on kinin peptide levels in blood, urine, and tissues, which may be accounted for by the differential contributions of ACE and NEP to kinin peptide metabolism in the multiple compartments in which kinin peptide generation occurs. Measurement of the levels of individual kinin peptides has given important information about the operation of the kallikrein-kinin system and its role in physiology and disease states.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1995

Multienzymatic non ribosomal peptide biosynthesis: identification of the functional domains catalysing peptide elongation and epimerisation.

Peptide synthetases are multienzymatic complexes that synthesize bioactive peptides molecules by the thiotemplate mechanism. Comparison of the known sequences of peptide synthetases led us to the identification of a 350 amino acids domain catalysing elongation and containing the motif HHxxxDG. This motif is present as many times as acyltransfer or epimerisation reactions occur during biosynthesis of the peptide. The distance between this motif and the phosphopantetheinyl attachment site is nearly invariant. An identical motif is found in other enzymes effecting acyl transfer such as chloramphenicol acetyltransferase from Tn9 and dihydrolipoamide acyltransferase. Altogether, the HHxxxDG motif may constitute the signature of a superfamily sharing a common catalytic mechanism based on the acid-base properties of the second histidine for effecting acyl transfer or peptide epimerisation.

Acyltransferases↗

PubMed1995

Highly conserved N-methyltransferases as an integral part of peptide synthetases.

The methyltransferase portion of the N-methyl-peptide-synthetase gene, synthesizing enniatin from Fusarium sambucinum, was amplified with the polymerase chain reaction (PCR) using primers derived from the highly conserved sequences of the flanking peptide synthetase domain. The deduced amino acid sequence of the product shares high similarity to the 430 amino acid methyltransferase portion of enniatin synthetase of Fusarium scirpi and the corresponding portions of another fungal peptide synthetase catalyzing the biosynthesis of the N-methylated cyclopeptide cyclosporin. As the methyltransferase portions show only local similarity to motifs apparently conserved within methyltransferases, the segments of peptide synthetases involved in the biosynthesis of bioactive peptides represent a new class of S-adenosyl-L-methionine dependent methyltransferases.

Amino Acid Sequence↗

PubMed1989

Bioactive conformation of linear peptides in solution: an elusive goal?

Bioactive peptides of natural origin have, in general, short linear sequences, and are characterized by a large conformational flexibility. It is very difficult to study their conformation in solution since they exist, almost invariably, as a complex mixture of numerous conformers, most of which are extended. The so-called bioactive conformation may be one of them, although the solvents used in solution studies often have properties drastically different from those of the biological system in which the peptide acts. There is, however, no simple way of identifying the bioactive conformation amid the many existing conformers. It is possible to approach a solution to this problem using two distinct strategies: (a) Limiting the conformational freedom of the peptide, e.g., by increasing the viscosity of the solution and decreasing the temperature, in the assumption that the bioactive conformation is, even slightly, more stable than the others. (b) Trying to mimic in solution the physicochemical features of the more reliable receptor models. These two approaches will be illustrated with examples taken mainly from opioid peptides.

Amino Acid Sequence↗

PubMed2005

Application of the "codon-shuffling" method. Synthesis and selection of de novo proteins as antibacterials.

Library-based methods of non-rational and part-rational designed de novo peptides are worthy beacons in the search for bioactive peptides and proteins of medicinal importance. In this report, we have used a recently developed directed evolution method called "codon shuffling" for the synthesis and selection of bioactive proteins. The selection of such proteins was based on the creation of an inducible library of "codon-shuffled" genes that are constructed from the ligation-based assembly of judiciously designed hexamer DNA duplexes called dicodons. Upon induction with isopropyl 1-thio-beta-D-galactopyranoside, some library members were found to express dicodon-incorporated proteins. Because of this, the host cells, in our case Escherichia coli, were unable to grow any further. The bactereostatic/lytic nature of the dicodon proteins was monitored by growth curves as well as by zone clearance studies. Transmission electron microscopy of the affected cells illustrated the extent of cell damage. The proteins themselves were overexpressed as fusion partners and subsequently purified to homogeneity. One such purified protein was found to strongly bind heparin, an indication that the interaction of the de novo proteins may be with the nucleic acids of the host cell, much like many of the naturally occurring antibacterial peptides, e.g. Buforin. Therefore, our approach may help in generating a multitude of finely tuned antibacterial proteins that can potentially be regarded as lead compounds once the method is extended to pathogenic hosts, such as Mycobacteria, for example.

Amino Acid Sequence↗

PubMedDate not supplied

Isolation and quantitation of several new peptides from the canine neurotensin/neuromedin N precursor.

Using antisera towards the bioactive peptides, neurotensin and neuromedin N, as well as towards the N-terminal and C-terminal regions of their shared 170-residue precursor, peptides representing various portions of the precursor were isolated from extracts of canine ileum. In total, seven peptides were isolated, two of which had not been previously identified. One was the C-terminal tail of the precursor (Gly-Ser-Tyr-Tyr-Tyr) and the other was the tail peptide extended N-terminally to include neurotensin (Glp-Leu-Tyr-Glu-Asn-Lys-Pro-Arg-Arg-Pro-Tyr-Ile-Leu-Lys-Arg-Gly-Ser-Tyr -Tyr- Tyr). By comparing the measured concentrations for each of the identified peptides, it was established that processing at the three Lys-Arg cleavage sites within the precursor did not occur to the same extent. Cleavage at the N-terminus of neuromedin N was approximately 10% complete, that between neurotensin and the tail was approximately 90% complete, and that between neuromedin N and neurotensin was approximately 95% complete. Three immunoreactive proteins were also identified by immunochemical and chromatographic analyses: N-terminally extended neuromedin N (125 residues), N-terminally extended neurotensin (140 residues), and the entire 147-residue precursor. It was concluded that neurotensin, tail and large molecular neuromedin N were the primary products of processing for this precursor in canine ileum, while minor products included neuromedin N, neurotensin tail, and large molecular neurotensin.

Amino Acid Sequence↗

PubMed2003

Two novel Bv8-like peptides from skin secretions of the toad Bombina maxima.

Two novel bioactive peptides were purified from skin secretions of the toad Bombina maxima. The partial N-terminal sequences of these two peptides were determined by automated Edman degradation. This allowed the cloning of full-length cDNAs encoding these two peptides from a cDNA library prepared from the toad skin. The deduced complete amino acid sequences indicate that both peptides are composed of 77 amino acids. A FASTA search in the databanks revealed that they exhibit 86-91% sequence identity with Bv8, a peptide originally isolated from skin secretions of Bombina variegata. They were thus named as Bv8-like peptide 1 (Bv8-LP1) and Bv8-like peptide 2 (Bv8-LP2), respectively. Sequence differences between Bv8-LP1 and 2 were due to six amino acid substitutions at positions 6, 11, 23, 24, 62 and 63. Bv8-LP1 and 2 differed from Bv8 with eleven and seven amino acid substitutions, respectively. Like Bv8, Bv8-LP1 and 2 possessed contractile activity on isolated guinea pig ileum. Additionally, they stimulated contraction of rabbit aortic rings in a dose-dependent manner at nanomolar concentrations.

Amino Acid Sequence↗

PubMed2003

Nonribosomal peptides: from genes to products.

The ability to synthesize nonribosomally small bioactive peptides that find application in modern medicine is widely spread among microorganisms. As broad as the spectrum of biological activities is the structural diversity of these peptides, which are mostly cyclic or branched cyclic compounds containing non-proteinogenic amino acids, small heterocyclic rings and other unusual modifications in the peptide backbone. They are synthesized by multimodular enzymes, the so-called nonribosomal peptide synthetases (NRPSs), from simple building blocks. Biochemical and genetic studies have unveiled the key principles of nonribosomal peptide syntheses, as well as the realization of many structural features of these peptides. This review focuses on recent results in NRPS research and highlights how this knowledge can be exploited for biotechnological purposes. In addition, possibilities and limitations for prediction of structural features of uncharacterized NRPSs and approaches for their engineering are discussed.

Amino Acid Sequence↗

PubMed2005

A folding-dependent mechanism of antimicrobial peptide resistance to degradation unveiled by solution structure of distinctin.

Many bioactive peptides, presenting an unstructured conformation in aqueous solution, are made resistant to degradation by posttranslational modifications. Here, we describe how molecular oligomerization in aqueous solution can generate a still unknown transport form for amphipathic peptides, which is more compact and resistant to proteases than forms related to any possible monomer. This phenomenon emerged from 3D structure, function, and degradation properties of distinctin, a heterodimeric antimicrobial compound consisting of two peptide chains linked by a disulfide bond. After homodimerization in water, this peptide exhibited a fold consisting of a symmetrical full-parallel four-helix bundle, with a well secluded hydrophobic core and exposed basic residues. This fold significantly stabilizes distinctin against proteases compared with other linear amphipathic peptides, without affecting its antimicrobial, hemolytic, and ion-channel formation properties after membrane interaction. This full-parallel helical orientation represents a perfect compromise between formation of a stable structure in water and requirement of a drastic structural rearrangement in membranes to elicit antimicrobial potential. Thus, distinctin can be claimed as a prototype of a previously unrecognized class of antimicrobial derivatives. These results suggest a critical revision of the role of peptide oligomerization whenever solubility or resistance to proteases is known to affect biological properties.

Animals↗

PubMed1987

The role of secretory granules in peptide biosynthesis.

There are many events in the posttranslational processing of bioactive peptides that occur in secretory granules and not to any great extent in other cellular organelles and that do not appear as modifications of the structure of many conventional neurotransmitters. In addition, at least two very important steps are unique to peptide-containing granules: (1) the peptides must begin their trek to the secretory granule in the RER as a larger precursor, rather than being taken up as a finished or nearly finished product into a mature granule; (2) there is at least one crucial sorting step on the way from the RER to the secretory granule that must occur faithfully before the peptide correctly appears in the granule. As for small molecules such as the catecholamines, the posttranslational processing enzymes and any required cofactors must also be put into the granules if the final events of processing are to occur with fidelity. Many of the posttranslational processing enzymes are only beginning to be identified. It is clear from these studies on purified PAM and peptide alpha-amidation as it occurs in cells that correlating test tube studies with the functioning of secretory granules is a worthwhile, if difficult, pursuit. The unique milieu inside the granule is difficult to mimic in a test tube. Transfection of peptide-producing cells with cDNAs encoding precursors with specific alterations in processing sites offers perhaps the best way to interface the studies of secretory granules and the posttranslational processing enzymes that mediate those functions.

Animals↗

PubMed2026

Bioactive macromolecules in LAB-fermented cereals: Mechanisms of formation, functional properties, and health benefits.

Cereal and pseudo-cereal based fermented food products represent a substantial segment of global diet, nutrition as well as food security. Fermentation, especially by Lactic Acid Bacteria (LAB) increases the nutritional and functional values of foods by increasing palatability, bioavailability and minimizing antinutritional factors. LAB plays a pivotal role in synthesizing bioactive peptides, vitamins, minerals and reducing anti-nutrients parallelly. This review elucidates the mechanism through which LAB revamping nutritional macromolecules, such as peptides and polysaccharides, during fermentation and their role in the development of traditional as well as modern fermented foods. Additionally, these fermented foods have been associated with several health benefits. Recent advancement in biotechnology such as genome sequencing, functional genomics, and AI-assisted bioinformatics, have significantly enhanced our understanding of the diversity of LAB, the metabolism, and adaptation mechanisms. The combination of in silico and experimental methods has enabled the development of novel food enzymes as well as highly precise fermentation processes. Together with new innovations, growing demands for quality, consistency, safety as well as health benefits point out the significance of continued research. More studies employing both conventional and modern methods are necessary to explore these food groups completely and achieve better food quality, increased nutrition, more health benefits and comprehensive socioeconomic advantages.

Bioactive macromolecules↗

PubMed2005

Monitoring the neuropeptide metabolites by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry.

The developments of bio-analytical methods for analyzing bioactive peptides are of paramount importance. Neuropeptides and their bioactive fragments play a vital role in the regulation of many biological processes and diseases. This paper presents the use of matrix-assisted laser desorption/ionization (MALDI) time-of-flight (TOF) mass spectrometry (MS) method for monitoring neuropeptides along with their degradation products in plasma samples from cancer patients. The neuropeptides focused in this study were beta-endrophin, substance P, and bradykinin. The method involves the enzyme digestion of the neuroactive peptides followed by MALDI-MS sample preparation and subsequent acquisition of the MS spectral data. The mass spectral profile identifies most of the C-terminal and N-terminal peptides, and the mass accuracy was in the range of -1.68 to 1.46 Da with the mass spectrometer utilised. Analysis of the neuropeptide degradation patterns from the cancer patients were compared with the controls showed similar results. The study reveals that this approach can be used to identify the enzymatic digestion products of protein.

Bradykinin↗

PubMed1998

Cathepsin D is a good candidate for the specific release of a stable hemorphin from hemoglobin in vivo: VV-hemorphin-7.

Hemorphin peptides, issued from hemoglobin, are emerging as endogenous bioactive peptides derived from in vivo tissular degradation of hemoglobin. In order to find the enzymes which could be implicated in the in vivo release of these peptides, the major lysosomal enzyme cathepsin D was selected, and a study of its activity towards hemoglobin and hemorphins was performed. In this paper, it is shown that according to the primary specificity of cathepsin D towards hemoglobin, this enzyme could constitute a good candidate for the in vivo release of two hemorphins: LVV-hemorphin-7 and VV-hemorphin-7. Moreover, these products, especially VV-hemorphin-7, are resistant to an extended cleavage by the enzyme. Although LVV-hemorphin-7 exhibits a lower resistance, an extended incubation with cathepsin D led to the release of the stable peptide VV-hemorphin-7.

Amino Acid Sequence↗

PubMed1993

Synthetic peptide combinatorial libraries (SPCLs): identification of the antigenic determinant of beta-endorphin recognized by monoclonal antibody 3E7.

The use of synthetic peptide combinatorial libraries (SPCLs), each composed of tens of millions of peptides, is described here for the identification of bioactive peptides. The identification of optimal peptide sequences is achieved through the screening of SPCLs in solution, each element of which is composed of more than 10(5) nonsupport-bound peptides in approximately equimolar representation, along with an iterative synthesis and screening process. Using an SPCL composed in total of 52 128 400 nonacetylated hexapeptides, along with an iterative selection process based on competitive ELISA, we identified the antigenic determinant of beta-endorphin recognized by monoclonal antibody (mAb) 3E7. These results will be compared with the results found by others investigating mAb 3E7 using different peptide library approaches.

Amino Acid Sequence↗

PubMed2005

Ubiquitin and ubiquitin-derived peptides as substrates for peptidylglycine alpha-amidating monooxygenase.

Ubiquitin (Ub) and the ubiquitin-like proteins (UBLs) mediate an array of cellular functions. These proteins contain a C-terminal glycine residue that is key to their function. Oxidative conversion of C-terminal glycine-extended prohormones to the corresponding alpha-amidated peptide is one step in the biosynthesis of bioactive peptide hormones. The enzyme catalyzing this reaction is peptidylglycine alpha-amidating monooxygenase (PAM). We report herein that Ub is a PAM substrate with a (V/K)(amidation) that is similar to other known peptide substrates. This work is significant because PAM and the UBLs co-localize to the hypothalamus and the adrenal medulla and are both over-expressed in glioblastomas.

Amino Acid Sequence↗

PubMed2002

Enzymatic degradation of luteinizing hormone releasing hormone (LHRH) by mucosal homogenates from the intestine of the common brushtail possum (Trichosurus vulpecula).

The peptidolytic activity of fresh and frozen mucosal homogenates from five regions (duodenum, jejunum, ileum, caecum and colon) of possum intestine from Trichosurus vulpecula towards human Luteinizing Hormone Releasing Hormone (LHRH) was investigated. The rank of order of specific peptidolytic activity of the mucosal homogenates was jejunum > ileum > caecum> duodenum = colon, with a 3 to 4 fold difference between the least and the most active segment in both frozen and fresh samples. The formation of peptides LHRH (1-3), LHRH (1-4) and LHRH (1-5) suggest endopepetidase-24.18, endopeptidase-24.15 and angiotensin converting enzyme (ACE) might be responsible for the peptide degradation in mucosal homogenates. The inhibition of LHRH degradation by mucosal homogenates was evaluated in four regions (jejunum, ileum, caecum and colon) of possum intestine. Ethylenediaminetetraacetic acid (EDTA, 5 mM), sodium deoxycholate (SDA, 10 mM) and bacitracin (3.5 or 9 mM) inhibited the degradation of LHRH in mucosal homogenates from small intestine and hindgut. However, the serine protease inhibitor, soybean trypsin-chymotrypsin inhibitor (SBTI), did not prevent degradation of LHRH. It is concluded that combining peptides with inhibitors may enhance oral delivery of bioactive peptides or proteins to possums.

Animals↗

PubMed2001

Purification of novel peptide antibiotics from human milk.

A strategy was established for the identification of novel antimicrobial peptides from human milk. For the generation of bioactive peptides human milk was acidified and proteolyzed with pepsin simulating the digest in infants stomachs. Separation of proteins and resulting fragments was performed by means of reversed-phase chromatography detecting the antimicrobial activity of each fraction using a sensitive radial diffusion assay. In order to avoid the purification of the known abundant antimicrobial milk protein lysozyme, it was identified in HPLC fractions by its enzymatic activity and by matrix-assisted laser desorption ionization-mass spectrometry (MALDI-MS). On condition that lysozyme was not detectable and antibacterial activity of HPLC fractions was caused by a peptide, which was confirmed by proteolytic cleavage leading to a loss of activity, further purification was performed by consecutive chromatographic steps guided by the antibacterial assay. Using this strategy, an as yet unknown casein fragment exhibiting antimicrobial activity was purified in addition to antimicrobial lactoferrin fragments. The new antimicrobial peptide resembles a proteolytic fragment of human casein-K (residues 63-117) and inhibits the growth of gram-positive, gram-negative bacteria, and yeasts. Our results confirm that antimicrobially-active peptides are liberated from human milk proteins during proteolytic hydrolysis and may play an important role in the host defense system of the newborn.

Amino Acid Sequence↗