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PubMed2002

Enzymatic activity of soluble and membrane tethered peptide pro-hormone convertase 1.

Pro-hormone convertases PC1 and PC2 perform endoproteolytic cleavages of precursors in peptide-containing secretory granules. PC1 and PC2 are soluble, secreted with bioactive peptides. Evolutionarily related PCs have membrane tethers, not secreted. We tethered PC1 to the transmembrane-cytoplasmic domains (CD) of a granule enzyme (peptidylglycine-alpha-amidating monooxygenase; PAM) and Golgi-localized PC8. The tethered PC1 is far more stable to elevated temperature and denaturants than soluble PC1, and more active. Both tethers allow PC1 to visit the cell surface transiently, cleaving soluble molecules outside the cell. Both membrane-bound PC1 chimeras cleave membrane PAM into soluble active fragments when PAM is expressed on adjacent cells.

Animals↗

PubMed2003

Ultrastructural localization of aminopeptidase A/angiotensinase and placental leucine aminopeptidase/oxytocinase in chorionic villi of human placenta.

AIMS: Membrane-bound aminopeptidases in human placenta are thought to be involved in maintaining homeostasis during pregnancy by metabolizing bioactive peptides such as oxytocin and angiotensin at the interface between the fetus and mother. Because determining the precise localization of these enzymes is required to support this notion, we investigated the ultrastructural localization of two principal enzymes, aminopeptidase A (APA; EC 3.4.11.7)/angiotensinase and placental leucine aminopeptidase (P-LAP; EC 3.4.11.3)/oxytocinase in human first trimester and full-term placenta. METHODS: Immunohistochemical analysis using anti-P-LAP and anti-APA antibodies was performed on ultrathin frozen sections of fixed human placental villi. RESULTS: Transmission immunoelectron microscopy revealed that both enzymes were expressed on the surface of apical microvilli of syncytiotrophoblast cells and, to a lesser extent, on the basal infoldings. The location of the two enzymes did not vary between the first trimester and full-term placenta sections, while the staining intensities were slightly enhanced in full-term villi. CONCLUSIONS: Our observation that P-LAP and APA are present on the microvilli, which is a site of interaction between the mother and fetus, suggests possible involvement of these enzymes in cleaving peptide hormones from the fetus and mother in order to regulate bioactivity.

Adult↗

PubMed2000

Breast cancer growth inhibition by delivery of the MDGI-derived peptide P108.

Mammary derived growth inhibitor (MDGI) is a member of the family of cytoplasmic fatty acid binding proteins (FABPs), which bind hydrophobic ligands such as fatty acids, retinoids, eicosanoids and prostaglandines. MDGI and an 11 amino acid MDGI-derived conserved C-terminal peptide (P108) inhibits growth of normal mammary epithelial cells in tissue and organ culture, but fails to inhibit proliferation of many breast cancer cell lines in vitro. Here, the effects of peptide P108 on tumor growth of MCF-7, MDA-MB468 and MDA-MB231 human breast cancer cell lines in nude mice were tested. To deliver P108 into tumors, a novel peptide production system was applied for expression and secretion of small bioactive peptides in mammalian cells. Functional differentiation was observed in MCF-7 and MDA-MB468 cells upon P108 expression. In addition, EGF-dependent colony formation in soft agar by MDA-MB468 cells was inhibited by secreted P108. Tumor growth in athymic nude mice was suppressed in all three cell lines tested. Furthermore, P108 expressed by MCF-7/P108 cells caused paracrine tumor growth inhibition of MDA-MB231 cells. These results indicate that breast cancer inhibition by P108 is independent of binding to hydrophobic ligands and is perhaps mediated by interference with EGF-dependent signaling pathways.

Amino Acid Sequence↗

PubMed1997

Alpha coat protein COPA (HEP-COP): presence of an Alu repeat in cDNA and identity of the amino terminus to xenin.

We previously sequenced the 4333-nucleotide cDNA of the COPA (HEP-COP) gene which encodes the human homologue of the alpha-subunit of the coatomer protein complex, involved in intracellular protein transport. Within the 3' untranslated region at nucleotides 4049-4333 was observed an Alu repeat containing conserved A and B block elements, and showing high homology to the human Alu-Sx subfamily consensus sequence. Upstream of the Alu repeat were noted a TATA box, a CAAT motif and two activating transcription factor (ATF)-like binding sites, which represent putative regulatory elements directing Alu transcription. In addition, the 25 and 35 N-terminal amino acid residues of COPA and its bovine homologue were identical to xenin-25 and proxenin, respectively. Xenin-25 is a gastrointestinal hormone that stimulates exocrine pancreatic secretion. This peptide is related to xenopsin, neurotensin and neuromedin N which are bioactive peptides derived from larger precursors via proteolytic cleavage by cathepsin E at processing sites determined by conserved C-terminal sequences, i.e. proline/valine-X-X-hydrophobic amino acid. Given the conformity of the C-terminal residues of xenin-25 (PWIL) and of its progenitor molecule, proxenin (VIQL), it is proposed that these peptides are generated by a similar mechanism of post-translational modification involving a parent precursor represented by the alpha-subunit of coatomer.

Base Sequence↗

PubMed1996

Des-(27-31)C-peptide. A novel secretory product of the rat pancreatic beta cell produced by truncation of proinsulin connecting peptide in secretory granules.

Insulin and connecting peptide (C-peptide) are produced in equimolar amounts during proinsulin conversion in the pancreatic beta cell secretory granule. To determine whether insulin and C-peptide are equally stable in beta cell granules (and thus secreted in equimolar amounts), neonatal and adult rat beta cells were pulse-chased, and radiolabeled insulin and C-peptide analyzed by high performance liquid chromatography. A novel truncated C-peptide was identified and shown by mass spectrometry to be des-(27-31)C-peptide (loss of 5 C-terminal amino acids). Des-(27-31)C-peptide is a major beta cell secretory product, accounting for 37.4 +/- 1.6% (neonatal) and 8.5 +/- 0.6% (adult) of total labeled C-peptide in secretory granules after 10 h of chase. Des-(27-31)C-peptide is also secreted in a glucose-sensitive manner from the perfused adult rat pancreas, accounting for approximately 10% of total C-peptide immunoreactivity secreted. Human C-peptide is also a substrate for truncation in granules. Thus, when human proinsulin was expressed (infection with recombinant adenovirus) in transformed (INS) rat beta cells, human des-(27-31)C-peptide was secreted along with the intact human peptide and both intact and truncated rat C-peptide. In addition to truncation, 33.1 +/- 1.2% of C-peptide in neonatal but not adult rat beta cell granules was further degraded. Such degradation was completely inhibited by ammonium chloride (known to neutralize intra-granular pH), whereas truncation was only partially inhibited by approximately 50%. In conclusion, a novel beta cell secretory product, des-(27-31)C-peptide, has been identified and should be considered as a potential bioactive peptide. Both truncation and degradation of C-peptide are responsible for non-equimolar secretion of insulin and C-peptide in rat beta cells.

Aging↗

PubMed1985

Endogenous opioids and related peptides: from molecular biology to clinical medicine. The Sir Henry Dale lecture for 1985.

Advances in techniques in molecular biology have facilitated the research into endogenous opioids and related peptides in several ways. The organization and expression of genes and the primary structure of three precursor proteins of opioid peptides have been elucidated. These studies predicted the presence of potentially bioactive peptides, which has been confirmed by later studies. Advances in techniques in protein chemistry have helped to elucidate the distribution and molecular forms of endogenous opioids and related peptides in the body, and the processing of precursor proteins. Studies on the function of these peptides have shown a broad spectrum of actions. Leumorphin, a newly identified peptide, has been shown to exhibit unique biological activities. In spite of extensive studies, the physiological and pathophysiological significance of opioid peptide systems are not yet completely understood. This is mainly due to the paucity of our knowledge about opioid receptors. Further studies on the subtypes of opioid receptors will help to elucidate all aspects of the function of endogenous opioids and related peptides.

Animals↗

PubMed2006

The cryptome: a subset of the proteome, comprising cryptic peptides with distinct bioactivities.

There is increasing evidence that proteolytic cleavage gives rise to 'hidden' peptides with bioactivities that are often unpredicted and totally distinct to the parent protein. So far, the liberation of these cryptic peptides, or crypteins, has been shown to be prevalent in proteins associated with endocrine signalling, the extracellular matrix, the complement cascade and milk. A broad spectrum of proteases has been implicated in the generation of natural crypteins that appear to play a role in modulating diverse biological processes, such as angiogenesis, immune function and cell growth. The proteolytic liberation of crypteins with novel activities represents an important mechanism for increasing diversity of protein function and potentially offers new opportunities for protein-based therapeutics.

Angiogenesis Inhibitors↗

PubMed2000

A monoclonal antibody directed against the neurokinin-1 receptor contains a peptide sequence with similar hydropathy and functional properties to substance P, the natural ligand for the receptor.

Monoclonal antibody (mAb) PS12, obtained using the complementary peptide methodology, mimics the neuropeptide substance P (SP) in recognizing the SP-binding domain of the neurokinin-1 receptor (NK1R) and eliciting production of polyclonal antibodies cross-reacting with SP with a high affinity (Déry et al., 1997. J. Neuroimmunol. 76, 1-9). The aim of the present study was to investigate which structural features of mAb PS12 might account for this molecular mimicry. Cloning and sequencing of variable regions of both light (VL) and heavy (VH) chains of this 'SP-like' antibody did not indicate any primary sequence homology between SP and any antibody region. Instead, they revealed a striking similarity between the hydropathic profile of SP and that of an 11-amino-acid region in the light chain encompassing the second complementarity determining region (CDR2). When applied to CHO cells expressing the human NK1R, a synthetic extended 17-amino-acid peptide (denoted CDR2L) corresponding to this VL region inhibited the high-affinity binding of radiolabeled SP and antagonized the SP-induced inositol phosphate production. Moreover, a re-examination of the sequences of several antibodies that previously served in the design of CDR-derived bioactive peptides indicated that these antibodies also carried the hydropathic image of the respective ligands that they mimic. In agreement with previous observations on artificial synthetic peptides, our data thus suggest that the molecular mimicry between natural proteins (i.e. antibody and hormone, for example) could be understood on a structural level directly related, at least in part, to hydropathic homology. These results could then guide the search for bioactive paratope-derived peptides of potential pharmacological interest. We also observed inverse hydropathy between multiple CDRs of mAb PS12 (including CDR3H and CDR3L) and the peptide epitope, confirming the importance of hydropathic complementarity in antigen-antibody interactions.

Amino Acid Sequence↗

PubMed1998

Post-translational N-glycosylation of a truncated form of a peptide processing enzyme.

Peptidylglycine alpha-amidating monooxygenase (PAM) catalyzes the carboxyl-terminal amidation of bioactive peptides through a two-step reaction involving the monooxygenase and lyase domains. PAM undergoes endoproteolytic cleavage in neuroendocrine cells in the lyase domain. To determine which of the two possible paired basic sites is utilized, truncated PAM proteins ending at these sites were stably expressed in Chinese hamster ovary cells. While characterizing the truncation mutants, it became apparent that N-glycosylation occurred post-translationally at the single site localized near the carboxyl terminus of the lyase domain. The post-translational N-glycosylation of this site does not require the newly synthesized protein to remain tightly bound to membranes. Both malfolded, secretion incompetent proteins and fully active, secreted proteins were subject to post-translational N-glycosylation.

Animals↗

PubMed1999

Characterization of a novel cDNA sequence encoding invertebrate tachykinin-related peptides isolated from the echiuroid worm, Urechis unicinctus.

Tachykinin is one of the most well-known bioactive peptides found in vertebrates, and tachykinin-related peptides have also been isolated from various invertebrate species. Urechistachykinin I (Leu-Arg-Gln-Ser-Gln-Phe-Val-Gly-Ser-Arg-NH(2)) and II (Ala-Ala-Gly-Met-Gly-Phe-Phe-Gly-Ala-Arg-NH(2)) were purified from the ventral nerve cords of echiuroid worm, Urechis unicinctus. In the present study, we described the characterization of a novel cDNA encoding the urechistachykinin precursor. Amino acid sequence analysis of the deduced polypeptide revealed that the urechistachykinin precursor included seven structurally related peptides, unlike mammalian tachykinin precursors which encode only one or two tachykinin peptides. This is the first identification of an invertebrate tachykinin-related peptide cDNA.

Amino Acid Sequence↗

PubMed1996

Identification of proxenin as a precursor of the peptide xenin with sequence homology to yeast and mammalian coat protein alpha.

Proxenin a precursor of the bioactive peptide xenin, was isolated from canine pancreas by HPLC and identified by mass spectrometry and sequence analysis as a pentatriacontapeptide with a molecular weight of 4035: Met Leu-Thr Lys-Phe-Glu-Thr-Lys-Ser-Ala-Arg-Val-Lys-Gly-Leu-Ser- Phe-His-Pro-Lys-Arg-Pro-Trp.Ile-Leu-Thr-Ser-Leu-His-Asn-Gly-Val-Ile-Glo- Leu-OH. Treatment with pepsin cleaved off 10 C-terminal amino acids and released xenin. Data base search showed amino acid sequence homology of xenin and proxenin with the sequence of coal protein alpha of yeast (62%) and humans (100%). Concentration of the coatomer complex from rabbit liver led to an equimolar enrichment of extractable proxenin. We conclude, therefore, that xenin and proxenin are peptide sequences highly conserved during evolution within the alpha-subunit of the coatomer.

Amino Acid Sequence↗

PubMed2004

Physicochemical properties of mixed micellar aggregates containing CCK peptides and Gd complexes designed as tumor specific contrast agents in MRI.

New amphiphilic molecules containing a bioactive peptide or a claw moiety have been prepared in order to obtain mixed micelles as target-specific contrast agents in magnetic resonance imaging. The first molecule, C(18)H(37)CONH(AdOO)(2)-G-CCK8 (C18CCK8), contains a C18 hydrophobic moiety bound to the C-terminal cholecystokinin octapeptide amide (CCK 26-33 or CCK8). The second amphiphilic compound, C(18)H(37)CONHLys(DTPAGlu)CONH(2) (C18DTPAGlu) or its gadolinium complex, (C18DTPAGlu(Gd)), contains the same C18 hydrophobic moiety bound, through a lysine residue, to the DTPAGlu chelating agent. The mixed aggregates as well as the pure C18DTPAGlu aggregate, in the presence and absence of Gd, have been fully characterized by surface tension measurements, FT-PGSE-NMR, fluorescence quenching, and small-angle neutron scattering measurements. The structural characterization of the mixed aggregates C18DTPAGlu(Gd)-C18CCK8 indicates a spherical arrangement of the micelles with an external shell of approximately 21 A and an inner core of approximately 20 A. Both the DTPAGlu(Gd) complexes and the CCK8 peptides point toward the external surface. The measured values for relaxivity in saline medium at 20 MHz proton Larmor frequency and 25 degrees C are 18.7 mM(-)(1) s(-)(1). These values show a large enhancement in comparison with the isolated DTPAGlu(Gd) complex.

Contrast Media↗

PubMed1989

Stimulation of hamster pulmonary neuroendocrine cells and associated peptides by repeated exposure to cigarette smoke.

Although the normal function of pulmonary neuroendocrine (PNE) cells containing bioactive peptides is poorly understood, various pulmonary diseases are associated with hyperplasia of these cells, and they also may be progenitors for small cell lung cancer in humans. In this study we have investigated the effects of subchronic cigarette smoke exposure in the hamster on the PNE cells and their peptide content. Daily exposure to standard research cigarette smoke for as long as 90 days led to progressively higher levels of serum calcitonin (iCT) as well as higher lung tissue iCT and the gastrin releasing-like peptides or mammalian bombesin (MB). Subsequent to a 30-day period during which there was no further exposure to smoke, serum levels returned to control levels, but the lung levels of both iCT and MB remained higher than control levels. Also, after the 90 days of exposure, immunocytochemistry revealed an increase in the number of iCT-containing PNE cells. This increase in the number of PNE cells correlated well with the increased iCT content of the lung tissue. We conclude that subchronic cigarette smoke exposure causes an increase in pulmonary levels of iCT and MB, which may be linked to the observed proliferative response of the PNE cells.

Animals↗

PubMed1991

Cultured astrocytes release proenkephalin.

Astrocytes as well as neurons express the mRNA encoding the opioid peptide precursor, proenkephalin. In neurons proenkephalin is cleaved intracellularly to yield smaller, bioactive peptides such as Met-enkephalin and Leu-enkephalin. By contrast, utilizing a combination of radioimmunoassay and chromatographic analysis, we report here that astrocytes cultured from neonatal rat brain contain primarily unprocessed proenkephalin and only small amounts of Met-enkephalin. Further, similar experiments with and without the inclusion of several peptidase inhibitors indicate that cultured astrocytes release proenkephalin itself into the medium where it may be subsequently cleaved to smaller peptide products. The release of intact proenkephalin by astrocytes suggests that the glial propeptide subserves a different function than neuronal proenkephalin and that opioid peptides may play novel roles in the central nervous system.

Animals↗

PubMed1993

Suppression of in vitro antibody production by corticotropin-releasing factor neurohormone.

Corticotropin-releasing factor (CRF) is a peptide hormone that regulates the synthesis of pro-opiomelanocortin (POMC)-derived bioactive peptides from the cells of both neuroendocrine system and immune system. In this study, the effect of CRF on in vitro production of antibodies was investigated. The peripheral blood mononuclear cells (MNC), at a concentration of 1 x 10(6) cells ml-1, from several healthy blood donors were stimulated to produce immunoglobulins with 25 micrograms ml-1 pokeweed mitogen (PWM) in the presence of different concentrations of CRF (10(-16) to 10(-7) M range). After 7 days of incubation, the cell cultures were centrifuged, and the supernatants quantified for IgG, IgM, and IgA by enzyme-linked immunosorbent assay (ELISA). At concentrations of 10(-13) M or greater, the CRF and three structurally related peptides (Tyr-CRF, alpha-helical CRF9-41, and sauvagine) caused a statistically significant (P < 0.001) suppression of the production of all three isotypes of Ig. At a antagonist: agonist ratio of as high as 100:1, the antagonist alpha-helical CRF9-41 did not antagonize the inhibitory action of CRF, instead it showed synergism with CRF by accentuating the CRF-induced suppression of IgG synthesis. This unexpected result may be due to the involvement of a subtype of CRF receptor which is insensitive to alpha-helical CRF. Moreover, the production of all three Ig isotypes was suppressed by rabbit antihuman-interleukin-1 (anti-IL-1) or rabbit antihuman-beta-endorphin (anti-beta E) or monocyte-depletion, but neither treatment significantly modified the CRF-induced suppression of antibody production.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed2001

Analysis of antimicrobial peptide interactions with hybrid bilayer membrane systems using surface plasmon resonance.

The lipid binding behaviour of the antimicrobial peptides magainin 1, melittin and the C-terminally truncated analogue of melittin (21Q) was studied with a hybrid bilayer membrane system using surface plasmon resonance. In particular, the hydrophobic association chip was used which is composed of long chain alkanethiol molecules upon which liposomes adsorb spontaneously to create a hybrid bilayer membrane surface. Multiple sets of sensorgrams with different peptide concentrations were generated. Linearisation analysis and curve fitting using numerical integration analysis were performed to derive estimates for the association (k(a)) and dissociation (k(d)) rate constants. The results demonstrated that magainin 1 preferentially interacted with negatively charged dimyristoyl-L-alpha-phosphatidyl-DL-glycerol (DMPG), while melittin interacted with both zwitterionic dimyristoyl-L-alpha-phosphatidylcholine and anionic DMPG. In contrast, the C-terminally truncated melittin analogue, 21Q, exhibited lower binding affinity for both lipids, showing that the positively charged C-terminus of melittin greatly influences its membrane binding properties. Furthermore the results also demonstrated that these antimicrobial peptides bind to the lipids initially via electrostatic interactions which then enhances the subsequent hydrophobic binding. The biosensor results were correlated with the conformation of the peptides determined by circular dichroism analysis, which indicated that high alpha-helicity was associated with high binding affinity. Overall, the results demonstrated that biosensor technology provides a new experimental approach to the study of peptide-membrane interactions through the rapid determination of the binding affinity of bioactive peptides for phospholipids.

Amino Acid Sequence↗

PubMed1999

Hyaluronic acid grafted with poly(ethylene glycol) as a novel peptide formulation.

Hyaluronic acids (HA) grafted with poly(ethylene glycol) (PEG) (PEG-g-HA) were synthesized. The materials characterization, enzymatic degradability and peptide (insulin) release from solutions of the copolymers were examined. Distribution of bioactive peptides within the polymer chain is well-known for combinations of PEG and polysaccharides as aqueous polymer two-phase systems. Insulin was preferentially partitioned into the PEG phase in a PEG/HA solution system. Enzymatic degradation of the copolymers was strongly dependent on the PEG content. Thermal analysis revealed that PEG-g-HA exhibited a variation in phase-separated structures depending on the PEG content. The solution of PEG-g-HA enabled insulin to remain in the PEG moieties dispersed in the HA matrix. Leakage of insulin from the copolymers was dependent upon the PEG content. Leakage rate of insulin from copolymer containing between 7 and 39% by weight of PEG were similar. A dramatic increase in leakage rate occurred when the PEG content was increased to greater than 39% by weight. It is considered that the loaded insulin was partitioned into the PEG moieties and became entangled with the PEG chains. The conformational change of insulin was effectively prevented in PEG-g-HA solutions, although insulin was denatured in storage of both phosphate buffered solution and HA solution. Such a heterogeneous-structured polymeric solution may be advantageous as an injectable therapeutic formulation for ophthalmic or arthritis treatment.

Biodegradation, Environmental↗

PubMed2006

Antihypertensive peptides derived from egg proteins.

There have been studies of antihypertensive peptides derived from food proteins, but very few described the production of bioactive peptides from egg proteins. The first 2 antihypertensive peptides isolated in egg were obtained by enzymatic hydrolysis of ovalbumin. They correspond to the sequences Phe-Arg-Ala-Asp-His-Pro-Phe-Leu (ovokinin) and Arg-Ala-Asp-His-Phe-Leu (ovokinin 2-7). Both exhibited endothelium-dependent vasodilatory activity. Ovokinin (2-7) had higher antihypertensive potency than ovokinin in spontaneously hypertensive rats (SHR). Modifications in the sequence of ovokinin (2-7) improved the bioavailability of this peptide. It was also demonstrated that different ovalbumin hydrolysates can inhibit angiotensin I-converting enzyme (ACE). We recently obtained an egg white hydrolysate that inhibited the enzyme in vitro. It was obtained by treating egg white with pepsin and it exhibited antihypertensive activity in SHR. Some ACE-inhibitory peptides obtained from this hydrolysate (Tyr-Arg-Glu-Glu-Arg-Tyr-Pro-Ile-Leu, Arg-Ala-Asp-His-Pro-Phe-Leu, and Ile-Val-Phe) also showed antihypertensive activity in these rats. The egg products mentioned could be used as functional food ingredients with potential therapeutic benefit in the prevention and treatment of hypertension.

Animals↗