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At least 181 records · Page 10Linked to original sources
PubMed1993

Chromostatin, a chromogranin A-derived bioactive peptide, is present in human pancreatic insulin (beta) cells.

Chromogranin A (CGA) is a secretory protein present in the adrenal medulla and in a variety of endocrine organs. This protein may serve as precursor for pancreastatin (PST) and for other biologically active peptides. Recently, chromostatin (CST), a CGA derivative, has been identified that possesses high biological activity. The cellular distribution of CST in various endocrine organs is completely unknown. Using immunohistochemistry on plastic sections, we investigated the occurrence and cellular distribution of CST, PST, and CGA in human endocrine pancreas of healthy and diseased states and in the adrenal medulla. In the normal and diabetic pancreas, CST immunoreactivity was localized exclusively in beta cells, which were mostly unreactive for PST and CGA. Both latter peptides were confined mainly to glucagon (alpha) cells. Insulinoma cells displayed strong insulin, PST, and CGA immunoreactivities, but they were faintly immunoreactive for CST or unreactive. Adrenal chromaffin cells exhibited strong immunoreactivity for CGA but lacked CST and PST immunoreactivities. Based on the peculiar distributive pattern of CST, PST, and CGA, we suggest that CGA is differentially processed in chromaffin and islet tissues and in insulinoma cells. The unique cellular localization of CST in the endocrine pancreas of normal and pathological conditions may indicate that CST is involved in beta-cell function.

Adrenal Medulla↗
PubMed1995

Processing of the precursors to neurotensin and other bioactive peptides by cathepsin E.

Cathepsin E (EC 3.4.23.34), an intracellular aspartic proteinase, was purified from monkey intestine by simple procedures that included affinity chromatography and fast protein liquid chromatography. Cathepsin E was very active at weakly acidic pH in the processing of chemically synthesized precursors such as the precursor to neurotensin/neuromedin, proopiomelanocortin, the precursor to xenopsin, and angiotensinogen. The processing sites were adjacent to a dibasic motif in the former two precursors and at hydrophobic recognition sites in the latter two. The common structural features that specified the processing sites were found in the carboxyl-terminal sequences of the active peptide moieties of these precursors; namely, the sequence Pro-Xaa-X'aa-hydrophobic amino acid was found at positions P4 through P1. Pro at the P4 position is thought to be important for directing the processing sites of the various precursor molecules to the active site of cathepsin E. Although the positions of Xaa and X'aa were occupied by various amino acids, including hydrophobic and aromatic amino acids, some of these had a negative effect, as typically observed when Glu/Arg and Pro were present at the P3 and P2 positions, respectively. Cathepsin D was much less active or was almost inactive in the processing of the precursors to neurotensin and related peptides as a result of the inability of the Pro-directed conformation of the precursor molecules to gain access to the active site of cathepsin D. Thus, the consensus sequence of precursors, Pro-Xaa-X'aa-hydrophobic amino acid, might not only generate the best conformation for cleavage by cathepsin E but might be responsible for the difference in specificities between cathepsins E and D.

Amino Acid Sequence↗
PubMed1997

Bioactive peptide design based on protein surface epitopes. A cyclic heptapeptide mimics CD4 domain 1 CC' loop and inhibits CD4 biological function.

The interaction between CD4 and major histocompatibility complex class II proteins provides a critical co-receptor function for the activation of CD4(+) T cells implicated in the pathogenesis of a number of autoimmune diseases and transplantation responses. A small synthetic cyclic heptapeptide was designed and shown by high resolution NMR spectroscopy to closely mimic the CD4 domain 1 CC' surface loop. This peptide effectively blocked stable CD4-major histocompatibility complex class II interaction, possessed significant immunosuppressive activity in vitro and in vivo, and strongly resisted proteolytic degradation. These results demonstrate the therapeutic potential of this peptide as a novel immunosuppressive agent and suggest a general strategy of drug design by using small conformationally constrained peptide mimics of protein surface epitopes to inhibit protein interactions and biological functions.

Amino Acid Sequence↗
PubMed2003

Virokinin, a bioactive peptide of the tachykinin family, is released from the fusion protein of bovine respiratory syncytial virus.

Tachykinins, an evolutionary conserved family of peptide hormones in both invertebrates and vertebrates, are produced by neuronal cells as inactive preprotachykinins that are post-translationally processed into different neuropeptides such as substance P, neurokinin A, and neurokinin B. We show here that furin-mediated cleavage of the bovine respiratory syncytial virus fusion protein results in the release of a peptide that is converted into a biologically active tachykinin (virokinin) by additional post-translational modifications. An antibody directed to substance P cross-reacted with the C terminus of mature virokinin that contains a classical tachykinin motif. The cellular enzymes involved in the C-terminal maturation of virokinin were found to be present in many established cell lines. Virokinin is secreted by virus-infected cells and was found to act on the tachykinin receptor 1 (TACR1), leading to rapid desensitization of this G protein-coupled receptor as shown by TACR1-green fluorescent protein conjugate translocation from the cell surface to endosomes and by co-internalization of the receptor with beta-arrestin 1-green fluorescent protein conjugates. In vitro experiments with isolated circular muscle from guinea pig stomach indicated that virokinin is capable of inducing smooth muscle contraction by acting on the tachykinin receptor 3. Tachykinins and their cognate receptors are present in the mammalian respiratory tract, where they have potent effects on local inflammatory and immune processes. The viral tachykinin-like peptide represents a novel form of molecular mimicry, which may benefit the virus by affecting the host immune response.

Animals↗
PubMed1998

Implications of gastric topical bioactive peptides in ammonia-induced acute gastric mucosal lesions in rats.

BACKGROUND: Ammonia, one of the pathogenic factors in Helicobacter pylori-induced mucosal injury, induces acute mucosal lesions in the rat glandular stomach. METHODS: The effect of ammonia administered intragastrically on gastric peptides was investigated in urethane-anesthetized rats. RESULTS: Gastric mucosal lesions were observed 5 min after 0.3% ammonia (4 ml/kg, intragastrically). Immunoreactive endothelin-1 (ET-1) and immunoreactive thyrotropin-releasing hormone (TRH) concentrations in the gastric wall decreased significantly 2 min and 5 min after ammonia, respectively. A significant increase in gastric juice immunoreactive ET-1 and TRH levels was reciprocally observed. The severity of gastric mucosal injury and changes in gastric immunoreactive ET-1 and TRH concentrations were shown to be concentration-dependent 30 min after ammonia. Atropine (5 mg/kg, intraperitoneally, -20 min) prevented ammonia-induced injury accompanied by a block of changes in gastric immunoreactive ET-1 and TRH concentrations. BQ-485 (ET(A) receptor antagonist; 2 mg/kg, subcutaneously) also abolished ammonia-induced lesions and gastric immunoreactive TRH changes. CONCLUSIONS: These findings suggested that gastric ET-1 and TRH play a role in ammonia-induced gastric mucosal injury mediated via a muscarine and an ET(A) receptor.

Ammonia↗
PubMed2003

Milk bioactive peptides and beta-casomorphins induce mucus release in rat jejunum.

Intestinal mucus is critically involved in the protection of the mucosa. An enzymatic casein hydrolysate and beta-casomorphin-7, a mu-opioid peptide generated in the intestine during bovine casein digestion, markedly induce mucus discharge. Because shorter mu-opioid peptides have been described, the effects of the opioid peptides in casein, beta-casomorphin-7, -6, -4, -4NH2 and -3, and of opioid neuropeptides met-enkephalin, dynorphin A and (D-Ala2,N-Me-Phe4,glycinol5)enkephalin (DAMGO) on intestinal mucus secretion were investigated. The experiments were conducted with isolated perfused rat jejunum. Mucus secretion under the influence of beta-casomorphins and opioid neuropeptides administered intraluminally or intra-arterially was evaluated using an ELISA for rat intestinal mucus. Luminal administration of beta-casomorphin-7 (1.2 x 10(-4) mol/L) provoked a mucus discharge (500% of controls) that was inhibited by naloxone, a specific opiate receptor antagonist. Luminal beta-casomorphin-6, -4 and -4NH2 did not modify basal mucus secretion, whereas intra-arterial administration of beta-casomorphin-4 (1.2 x 10(-6) mol/L) induced a mucus discharge. In contrast, intra-arterial administration of the nonopioid peptide beta-casomorphin-3 did not release mucus. Among the opioid neuropeptides, intra-arterial infusion of Met-enkephalin or dynorphin-A did not provoke mucus secretion. In contrast, beta-endorphin (1.2 x 10(-8) to 1.2 x 10(-6) mol/L) induced a dose-dependent release of mucus (maximal response at 500% of controls). DAMGO (1.2 x 10(-6) mol/L), a mu-receptor agonist, also evoked a potent mucus discharge. Our findings suggest that mu-opioid neuropeptides, as well as beta-casomorphins after absorption, modulate intestinal mucus discharge. Milk opioid-derived peptides may thus be involved in defense against noxious agents and could have dietary and health applications.

Animals↗
PubMed1991

Purification of a cysteine endopeptidase which is secreted with bioactive peptides from the epidermal glands of Xenopus laevis.

The purification is reported of an endopeptidase, XSCEP1 (Xenopus skin cysteine endopeptidase), present in skin secretions of Xenopus. The procedure involved an initial concentration of the enzyme by batchwise anion-exchange chromatography and ammonium sulphate precipitation. The proteolytic activity, determined with Z-Phe-Arg-Amc (Z, benzyloxycarbonyl; Amc, 7-amidomethylcoumarin) as substrate, was fractionated by gradient ion-exchange chromatography, yielding a major component which was purified to homogeneity by chromatography on an organomercury-agarose column. SDS/PAGE demonstrated the presence of a single protein with a molecular mass of 27 kDa. The purified enzyme, which possessed a pH optimum of 5.5, exhibited the properties of a cysteine endopeptidase; it was activated by dithiothreitol and EDTA and inhibited by the mechanism-based inhibitor trans-epoxysuccinyl-L-leucylamido(4-guanidino)butane. XSCEP1 exhibited a marked preference for substrates with a hydrophobic residue in the P1 position and arginine in the P2 position as opposed to a substrate with arginine residues in both positions. The enzyme was also able to cleave a Val-Arg-Gly sequence in a model substrate, reflecting cleavages undergone by a number of peptides present in Xenopus skin. The results point to a functional role for XSCEP1 as a putative processing enzyme.

Amino Acid Sequence↗
PubMed2000

Antiflammins. Bioactive peptides derived from uteroglobin.

Uteroglobin/Clara cell 10-kDa protein (UG/CC10) is a hormonally regulated small secretory protein that has a variety of in vitro and in vivo pharmacological effects. These include a potent anti-inflammatory activity and inhibitory effects on neutrophil migration, thrombin-induced platelet aggregation, in vitro chemoinvasion, as well as "tumor suppressor"-like effects and other properties. Several mechanisms of action have been proposed for these effects. Pharmacological properties suggest that UG itself or substances derived from it may be used as experimental drugs for several indications. The group of oligopeptides collectively known as "antiflammins" (AFs) were originally described in 1988. Their design was derived from the region of highest sequence similarity between UG and another group of proteins with anti-inflammatory properties, the lipocortins or annexins. Nanomolar concentrations of these peptides can reproduce several of the pharmacological activities of UG, including its in vivo anti-inflammatory effects and inhibition of platelet aggregation. The AFs have been safely and effectively used to suppress inflammation and fibrosis in several animal models. Progress in clarifying the mechanism of action of the AFs may facilitate the structure-based design of a novel class of potent anti-inflammatory, antichemotactic drugs.

Animals↗
PubMed1994

Subcellular distribution of proteolytic activities degrading bioactive peptides and analogues in the rat small intestinal and colonic enterocytes.

The objective of this study was to compare, in rat small intestinal and colonic enterocytes, subcellular distributions of activities degrading the large peptides, neurotensin, acetylneurotensin (8-13), GRF(1-29)NH2 (human growth hormone releasing factor fragment), (desNH2Tyr1,D-Ala2,Ala15)-GRF(1-29)NH2, insulin, and insulin B-chain. Proteolytic activities degrading individual peptides in the 10,000-g pellet, rich in intracellular organelles, 27,000-g pellet, rich in brush-border membrane, 100,000-g pellet, and 100,000-g supernatant, rich in cytosol, were determined and compared for both the small intestine and colon. In colonic fractions, the cytosol had highest activity (g protein)-1 degrading three out of four peptides tested, while in small intestinal fractions, the 27,000-g pellet had the highest activity (g protein)-1, degrading four out of five peptides tested. In both small intestine and colon, the cytosol had a higher percentage of total proteolytic activity degrading each of the above polypeptides and the highest insulin-degrading activity (g protein)-1. The results suggest that at pH 7.5, proteolytic activities (g protein)-1 in the fraction of subcellular organelles are much lower than those in cytosol and that cytosolic proteolytic activities degrading polypeptides and analogues are significant.

Amino Acid Sequence↗
PubMed1997

Amidation of bioactive peptides: the structure of peptidylglycine alpha-hydroxylating monooxygenase.

Many neuropeptides and peptide hormones require amidation at the carboxyl terminus for activity. Peptidylglycine alpha-amidating monooxygenase (PAM) catalyzes the amidation of these diverse physiological regulators. The amino-terminal domain of the bifunctional PAM protein is a peptidylglycine alpha-hydroxylating monooxygenase (PHM) with two coppers that cycle through cupric and cuprous oxidation states. The anomalous signal of the endogenous coppers was used to determine the structure of the catalytic core of oxidized rat PHM with and without bound peptide substrate. These structures strongly suggest that the PHM reaction proceeds via activation of substrate by a copper-bound oxygen species. The mechanistic and structural insight gained from the PHM structures can be directly extended to dopamine beta-monooxygenase.

Animals↗
PubMed1998

A bioactive peptide from the transmembrane 5-intracellular loop 3 region of the human 5HT1a receptor.

15 amino acid peptide from the transmembrane 5-intracellular loop 3 region of the human 5HT1a receptor produced concentration-dependent decreases in agonist binding. This result is consistent with a competitive interaction between peptide, receptor, and G protein at the receptor-G protein interface. Bombesin and a 13 amino acid peptide from the carboxyl terminus region of the receptor were inactive. Additionally, the peptide decreased forskolin-mediated cAMP elevation. Overall, these results suggest that amino acid residues from this region of the receptor are involved in receptor-G protein coupling and that G protein is activated by the receptor.

Animals↗
PubMed2005

Annexin 1 and its bioactive peptide inhibit neutrophil-endothelium interactions under flow: indication of distinct receptor involvement.

We have tested the effects of annexin 1 (ANXA1) and its N-terminal peptide Ac2-26 on polymorphonuclear leukocyte (PMN) recruitment under flow. Differential effects of the full-length protein and its peptide were observed; ANXA1 inhibited firm adhesion of human PMNs, while Ac2-26 significantly attenuated capture and rolling without effect on firm adhesion. Analysis of the effects of ANXA1 and Ac2-26 on PMN adhesion molecule expression supported the flow chamber results, with Ac2-26 but not ANXA1 causing l-selectin and PSGL-1 shedding. ANXA1 and its peptide act via the FPR family of receptors. This was corroborated using HEK-293 cells transfected with FPR or FPRL-1/ALX (the 2 members of this family expressed by human PMNs). While Ac2-26 bound both FPR and FPRL-1/ALX, ANXA1 bound FPRL-1/ALX only. ANXA1 and Ac2-26 acted as genuine agonists; Ac2-26 binding led to ERK activation in both FPR- and FPRL-1/ALX-transfected cells, while ANXA1 caused ERK activation only in cells transfected with FPRL-1/ALX. Finally, blockade of FPRL-1/ALX with a neutralizing monoclonal antibody was found to abrogate the effects of ANXA1 in the flow chamber but was without effect on Ac2-26-mediated inhibition of rolling. These findings demonstrate for the first time distinct mechanisms of action for ANXA1 and its N-terminal peptide Ac2-26.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Evidence for conservation and selection of upstream open reading frames suggests probable encoding of bioactive peptides.

BACKGROUND: Approximately 40% of mammalian mRNA sequences contain AUG trinucleotides upstream of the main coding sequence, with a quarter of these AUGs demarcating open reading frames of 20 or more codons. In order to investigate whether these open reading frames may encode functional peptides, we have carried out a comparative genomic analysis of human and mouse mRNA 'untranslated regions' using sequences from the RefSeq mRNA sequence database. RESULTS: We have identified over 200 upstream open reading frames which are strongly conserved between the human and mouse genomes. Consensus sequences associated with efficient initiation of translation are overrepresented at the AUG trinucleotides of these upstream open reading frames, while comparative analysis of their DNA and putative peptide sequences shows evidence of purifying selection. CONCLUSION: The occurrence of a large number of conserved upstream open reading frames, in association with features consistent with protein translation, strongly suggests evolutionary maintenance of the coding sequence and indicates probable functional expression of the peptides encoded within these upstream open reading frames.

3' Untranslated Regions↗
PubMed1992

Food contains the bioactive peptide, cyclo(His-Pro).

Cyclo(His-Pro) (CHP) is a cyclic dipeptide with numerous biological activities. As small di- and tripeptides may be absorbed intact when ingested orally, we were interested in examining several common foods for the presence of cyclo(His-Pro)-like immunoreactivity (CHP-LI). In all foods tested, CHP-LI was found at levels 5-1500 times those previously found in human plasma. This CHP-LI was identical to authentic CHP by immunoidentity and chromatographic behavior. We conclude that 1) CHP-LI is readily detectable in several common food sources; 2) this CHP-LI is indistinguishable from authentic CHP; and 3) it is likely the CHP-LI in foods is absorbed in quantities sufficient to cause elevations of CHP-LI in plasma to biologically significant levels.

Chromatography↗
PubMed1992

[Elucidation of biosynthetic process and regulation mechanism of bioactive peptides and their receptors].

To elucidate the mechanism of proinsulin induction by glucose, we determined the amount of proinsulin messenger ribonucleic acid (mRNA), the subcellular distribution of proinsulin mRNA and the transcriptional activity of proinsulin gene in isolated pancreatic islets of rat. From these results, we concluded that the stimulation of proinsulin synthesis was mainly regulated at the translational level. To elucidate the primary structure of vasoactive intestinal peptide (VIP) precursor, we determined the nucleotide sequence of VIP complementary deoxyribonucleic acid (cDNA). The entire amino acid sequence of the VIP precursor indicates that the precursor protein contains not only VIP but also PHI-like peptide. We also found that the induction of pro-VIP synthesis was achieved by enhancing the transcription rate of VIP gene. We also isolated fibroblast growth factor (FGF) receptor cDNA. The nucleotide sequence of FGF receptor cDNA indicates that the receptor is a transmembrane protein that contains extracellular immunoglobulin-like domains and an intracellular tyrosine kinase domain. We also found that the receptor had two isoforms of the extracellular domains and that the expression of the isoforms was regulated tissue-specifically.

Amino Acid Sequence↗