Journal articles on the topic 'Peptide toxin'
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1
Karauzum, Hatice, and Sandip Datta. "Immunization with superantigen-derived oligopeptides protect against S. aureus bacteremia (VAC8P.1058)." Journal of Immunology 194, no. 1_Supplement (May 1, 2015): 144.14. http://dx.doi.org/10.4049/jimmunol.194.supp.144.14.
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Abstract Staphylococcal superantigens are exotoxins that play a major role in disease pathogenesis. Using a T cell epitope prediction tool from the Immune Epitope Database Analysis Resource (IEDB) site, sequences within staphylococcal enterotoxin A and B (SEA, SEB) and Toxic Shock Syndrome Toxin with high affinity towards H2-Iab were identified and oligopeptides SEA_aa116-128, SEB_aa16-28 and TSST-1_aa212-224 were generated. C57BL/6 mice were immunized with a cocktail of oligopeptides or whole toxins in Al(OH)3. Serum samples from peptide-immunized mice tested positive towards individual peptides and whole toxins, however, samples from mice immunized with whole toxins did not bind to any of the peptides. To determine peptide-specific T cell response primed CD4 T cells isolated from spleens and total LNs of immunized mice were co-cultured with peptide-pulsed BMDCs and cytokine response was evaluated. Only cells of peptide-immunized mice resulted in elevated levels of IL-4, IL-5, IL-10, IL-13, GM-CSF, IFNg and TNFa, while cells obtained from whole toxin-immunized mice did not differ from baseline levels. To evaluate protective efficacy of peptides against toxin expressing strains, immunized mice were infected intravenously with MNHOCH (SEB+) or Newman (SEA+) and monitored up to 13 days. Mice that were infected with MNHOCH showed significantly extended survival compared to non-immunized mice (P=0.03). No significant difference in survival was observed when infected with strain Newman.
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Stepensky, David. "Pharmacokinetics of Toxin-Derived Peptide Drugs." Toxins 10, no. 11 (November 20, 2018): 483. http://dx.doi.org/10.3390/toxins10110483.
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Toxins and venoms produced by different organisms contain peptides that have evolved to have highly selective and potent pharmacological effects on specific targets for protection and predation. Several toxin-derived peptides have become drugs and are used for the management of diabetes, hypertension, chronic pain, and other medical conditions. Despite the similarity in their composition (amino acids as the building blocks), toxin-derived peptide drugs have very profound differences in their structure and conformation, in their physicochemical properties (that affect solubility, stability, etc.), and subsequently in their pharmacokinetics (the processes of absorption, distribution, metabolism, and elimination following their administration to patients). This review summarizes and critically analyzes the pharmacokinetic properties of toxin-derived peptide drugs: (1) the relationship between the chemical structure, physicochemical properties, and the pharmacokinetics of the specific drugs, (2) the major pharmacokinetic properties and parameters of these drugs, and (3) the major pharmacokinetic variability factors of the individual drugs. The structural properties of toxin-derived peptides affect their pharmacokinetics and pose some limitations on their clinical use. These properties should be taken into account during the development of new toxin-derived peptide drugs, and for the efficient and safe use of the clinically approved drugs from this group in the individual patients.
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da Silva, Daiane Laise, Rodrigo Valladão, Emidio Beraldo-Neto, Guilherme Rabelo Coelho, Oscar Bento da Silva Neto, Hugo Vigerelli, Adriana Rios Lopes, et al. "Spatial Distribution and Biochemical Characterization of Serine Peptidase Inhibitors in the Venom of the Brazilian Sea Anemone Anthopleura cascaia Using Mass Spectrometry Imaging." Marine Drugs 21, no. 9 (August 30, 2023): 481. http://dx.doi.org/10.3390/md21090481.
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Sea anemones are known to produce a diverse array of toxins with different cysteine-rich peptide scaffolds in their venoms. The serine peptidase inhibitors, specifically Kunitz inhibitors, are an important toxin family that is believed to function as defensive peptides, as well as prevent proteolysis of other secreted anemone toxins. In this study, we isolated three serine peptidase inhibitors named Anthopleura cascaia peptide inhibitors I, II, and III (ACPI-I, ACPI-II, and ACPI-III) from the venom of the endemic Brazilian sea anemone A. cascaia. The venom was fractionated using RP-HPLC, and the inhibitory activity of these fractions against trypsin was determined and found to range from 59% to 93%. The spatial distribution of the anemone peptides throughout A. cascaia was observed using mass spectrometry imaging. The inhibitory peptides were found to be present in the tentacles, pedal disc, and mesenterial filaments. We suggest that the three inhibitors observed during this study belong to the venom Kunitz toxin family on the basis of their similarity to PI-actitoxin-aeq3a-like and the identification of amino acid residues that correspond to a serine peptidase binding site. Our findings expand our understanding of the diversity of toxins present in sea anemone venom and shed light on their potential role in protecting other venom components from proteolysis.
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Maillère, B., J. Cotton, G. Mourier, M. Léonetti, S. Leroy, and A. Ménez. "Role of thiols in the presentation of a snake toxin to murine T cells." Journal of Immunology 150, no. 12 (June 15, 1993): 5270–80. http://dx.doi.org/10.4049/jimmunol.150.12.5270.
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Abstract We isolated and characterized two T hybridomas specific for a highly stable snake toxic protein. One hybridoma, called T1C9, is I-E(d)-restricted and stimulated by both the native and reduced and carboxymethylated (RCM) toxins and by synthetic fragments containing the region 24-36. The other hybridoma, called T1B2, is I-A(d)-restricted and stimulated by the native toxin, only. Neither the RCM toxin nor any of the initial synthetic peptides used in our study could stimulate it. We show that this lack of effect is associated with the presence, in the epitope-containing fragment, of irreversible blocking groups on cysteine residues. Indeed, when the fragment 32-49 has its cysteines involved in either intra-(32-49SS) or mixed disulfides, a stimulation of T1B2 was observed. Fixed APC do not present native toxin to either hybridomas but present RCM toxin to T1C9. Strikingly, fixed APC present the peptide 32-49SS to T1B2; however, we show that this is possible only because the peptide disulfide is reduced. The thiol dependence of this epitope suggests that the native toxin can stimulate T1B2 only after disulfide reduction. This reaction may constitute a major step during the processing of the toxin and more generally of any disulfide-containing Ag.
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Bahraoui, E. M., C. Granier, J. Van Rietschoten, H. Rochat, and M. el Ayeb. "Specificity and neutralizing capacity of antibodies elicited by a synthetic peptide of scorpion toxin." Journal of Immunology 136, no. 9 (May 1, 1986): 3371–77. http://dx.doi.org/10.4049/jimmunol.136.9.3371.
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Abstract Polyclonal antibodies raised against a synthetic peptide (sequence 50-59) of Androctonus australis Hector toxin II can neutralize the effects of toxin II in vivo. The antigenic specificities of anti-peptide and anti-toxin antibodies were compared by competitive aqueous phase radioimmunoassay by using 125I-toxin II, chemically modified or homologous toxins, and the synthetic peptide 50-59, either free or bound to bovine serum albumin (BSA). The antipeptide and anti-toxin antibodies had a comparable high affinity for the native toxin, but anti-peptide antibodies exhibited a lower binding capacity. Anti-peptide antibodies had a higher affinity for native toxin than for the peptide 50-59 bound to BSA, used as immunogen, and were unable to recognize the free peptide. These results suggest that it is necessary to restrict the conformational freedom of the immunizing peptide in order to obtain anti-peptide antibodies with a high affinity for the toxin. The lysine residue at position 58 of toxin II, essential for toxicity, appears to be immunogenic when immunization is with peptide 50-59 bound to BSA and not with the native toxin. This residue is antigenic in the native toxin, however, as shown by the anti-peptide antibodies.
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Liao, Qingyi, Xiangjin Kong, Guoqing Luo, Xiangyue Wu, Yinping Li, Qicai Liu, Cheng Tang, and Zhonghua Liu. "Molecular Diversity of Peptide Toxins in the Venom of Spider Heteropoda pingtungensis as Revealed by cDNA Library and Transcriptome Sequencing Analysis." Toxins 14, no. 2 (February 14, 2022): 140. http://dx.doi.org/10.3390/toxins14020140.
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The venoms of toxic animals are chemical pools composed of various proteins, peptides, and small organic molecules used for predation and defense, in which the peptidic toxins have been intensively pursued mining modulators targeting disease-related ion channels and receptors as valuable drug pioneers. In the present study, we uncovered the molecular diversity of peptide toxins in the venom of the spider Heteropoda pingtungensis (H. pingtungensis) by using a combinatory strategy of venom gland cDNA library and transcriptome sequencing (RNA-seq). An amount of 991 high-quality expressed sequence tags (ESTs) were identified from 1138 generated sequences, which fall into three categories, such as the toxin-like ESTs (531, 53.58%), the cellular component ESTs (255, 25.73%), and the no-match ESTs (205, 20.69%), as determined by gene function annotations. Of them, 190 non-redundant toxin-like peptides were identified and can be artificially grouped into 13 families based on their sequence homology and cysteine frameworks (families A–M). The predicted mature toxins contain 2–10 cysteines, which are predicted to form intramolecular disulfide bonds to stabilize their three-dimensional structures. Bioinformatics analysis showed that toxins from H. pingtungensis venom have high sequences variability and the biological targets for most toxins are unpredictable due to lack of homology to toxins with known functions in the database. Furthermore, RP-HPLC and MALDI-TOF analyses have identified a total of 110 different peptides physically existing in the H. pingtungensis venom, and many RP-HPLC fractions showed potent inhibitory activity on the heterologously expressed NaV1.7 channel. Most importantly, two novel NaV1.7 peptide antagonists, µ-Sparatoxin-Hp1 and µ-Sparatoxin-Hp2, were characterized. In conclusion, the present study has added many new members to the spider toxin superfamily and built the foundation for identifying novel modulators targeting ion channels in the H. pingtungensis venom.
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Hyland, Caroline, Laurent Vuillard, Colin Hughes, and Vassilis Koronakis. "Membrane Interaction of Escherichia coliHemolysin: Flotation and Insertion-Dependent Labeling by Phospholipid Vesicles." Journal of Bacteriology 183, no. 18 (September 15, 2001): 5364–70. http://dx.doi.org/10.1128/jb.183.18.5364-5370.2001.
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ABSTRACT The 1,024-amino-acid acylated hemolysin of Escherichia coli subverts host cell functions and causes cell lysis. Both activities require insertion of the toxin into target mammalian cell membranes. To identify directly the principal toxin sequences dictating membrane binding and insertion, we assayed the lipid bilayer interaction of native protoxin, stably active toxin, and recombinant peptides. Binding was assessed by flotation of protein-liposome mixtures through density gradients, and insertion was assessed by labeling with a photoactivatable probe incorporated into the target lipid bilayer. Both the active acylated hemolysin and the inactive unacylated protoxin were able to bind and also insert. Ca2+binding, which is required for toxin activity, did not influence the in vitro interaction with liposomes. Three overlapping large peptides were expressed separately. A C-terminal peptide including residues 601 to 1024 did not interact in either assay. An internal peptide spanning residues 496 to 831, including the two acylation sites, bound to phospholipid vesicles and showed a low level of insertion-dependent labeling. In vitro acylation had no effect on the bilayer interaction of either this peptide or the full-length protoxin. An N-terminal peptide comprising residues 1 to 520 also bound to phospholipid vesicles and showed strong insertion-dependent labeling, ca. 5- to 25-fold that of the internal peptide. Generation of five smaller peptides from the N-terminal region identified the principal determinant of lipid insertion as the hydrophobic sequence encompassing residues 177 to 411, which is conserved among hemolysin-related toxins.
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GREEN, Daniel, Suzi PACE, Suzanne M. CURTIS, Magdalena SAKOWSKA, Graham D. LAMB, Angela F. DULHUNTY, and Marco G. CASAROTTO. "The three-dimensional structural surface of two beta-sheet scorpion toxins mimics that of an alpha-helical dihydropyridine receptor segment." Biochemical Journal 370, no. 2 (March 1, 2003): 517–27. http://dx.doi.org/10.1042/bj20021488.
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An α-helical II—III loop segment of the dihydropyridine receptor activates the ryanodine receptor calcium-release channel. We describe a novel manipulation in which this agonist's activity is increased by modifying its surface structure to resemble that of a toxin molecule. In a unique system, native β-sheet scorpion toxins have been reported to activate skeletal muscle ryanodine receptor calcium channels with high affinity by binding to the same site as the lower-affinity α-helical dihydropyridine receptor segment. We increased the alignment of basic residues in the α-helical peptide to mimic the spatial orientation of active residues in the scorpion toxin, with a consequent 2—20-fold increase in the activity of the α-helical peptide. We hypothesized that, like the native peptide, the modified peptide and the scorpion toxin may bind to a common site. This was supported by (i) similar changes in ryanodine receptor channel gating induced by the native or modified α-helical peptide and the β-sheet toxin, a 10—100-fold reduction in channel closed time, with a ≤2-fold increase in open dwell time and (ii) a failure of the toxin to further activate channels activated by the peptides. These results suggest that diverse structural scaffolds can present similar conformational surface properties to target common receptor sites.
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Mitpuangchon, Natrada, Kwan Nualcharoen, Singtoe Boonrotpong, and Patamarerk Engsontia. "Identification of Novel Toxin Genes from the Stinging Nettle Caterpillar Parasa lepida (Cramer, 1799): Insights into the Evolution of Lepidoptera Toxins." Insects 12, no. 5 (April 29, 2021): 396. http://dx.doi.org/10.3390/insects12050396.
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Many animal species can produce venom for defense, predation, and competition. The venom usually contains diverse peptide and protein toxins, including neurotoxins, proteolytic enzymes, protease inhibitors, and allergens. Some drugs for cancer, neurological disorders, and analgesics were developed based on animal toxin structures and functions. Several caterpillar species possess venoms that cause varying effects on humans both locally and systemically. However, toxins from only a few species have been investigated, limiting the full understanding of the Lepidoptera toxin diversity and evolution. We used the RNA-seq technique to identify toxin genes from the stinging nettle caterpillar, Parasa lepida (Cramer, 1799). We constructed a transcriptome from caterpillar urticating hairs and reported 34,968 unique transcripts. Using our toxin gene annotation pipeline, we identified 168 candidate toxin genes, including protease inhibitors, proteolytic enzymes, and allergens. The 21 P. lepida novel Knottin-like peptides, which do not show sequence similarity to any known peptide, have predicted 3D structures similar to tarantula, scorpion, and cone snail neurotoxins. We highlighted the importance of convergent evolution in the Lepidoptera toxin evolution and the possible mechanisms. This study opens a new path to understanding the hidden diversity of Lepidoptera toxins, which could be a fruitful source for developing new drugs.
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Van Baelen, Anne-Cécile, Xavier Iturrioz, Marion Chaigneau, Pascal Kessler, Catherine Llorens-Cortes, Denis Servent, Nicolas Gilles, and Philippe Robin. "Characterization of the First Animal Toxin Acting as an Antagonist on AT1 Receptor." International Journal of Molecular Sciences 24, no. 3 (January 24, 2023): 2330. http://dx.doi.org/10.3390/ijms24032330.
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The renin-angiotensin system (RAS) is one of the main regulatory systems of cardiovascular homeostasis. It is mainly composed of angiotensin-converting enzyme (ACE) and angiotensin II receptors AT1 and AT2. ACE and AT1 are targets of choice for the treatment of hypertension, whereas the AT2 receptor is still not exploited due to the lack of knowledge of its physiological properties. Peptide toxins from venoms display multiple biological functions associated with varied chemical and structural properties. If Brazilian viper toxins have been described to inhibit ACE, no animal toxin is known to act on AT1/AT2 receptors. We screened a library of toxins on angiotensin II receptors with a radioligand competition binding assay. Functional characterization of the selected toxin was conducted by measuring second messenger production, G-protein activation and β-arrestin 2 recruitment using bioluminescence resonance energy transfer (BRET) based biosensors. We identified one original toxin, A-CTX-cMila, which is a 7-residues cyclic peptide from Conus miliaris with no homology sequence with known angiotensin peptides nor identified toxins, displaying a 100-fold selectivity for AT1 over AT2. This toxin shows a competitive antagonism mode of action on AT1, blocking Gαq, Gαi3, GαoA, β-arrestin 2 pathways and ERK1/2 activation. These results describe the first animal toxin active on angiotensin II receptors.
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Possani, L. D., B. M. Martin, I. Svendsen, G. S. Rode, and B. W. Erickson. "Scorpion toxins from Centruroides noxius and Tityus serrulatus. Primary structures and sequence comparison by metric analysis." Biochemical Journal 229, no. 3 (August 1, 1985): 739–50. http://dx.doi.org/10.1042/bj2290739.
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The complete primary structures of toxin II-14 from the Mexican scorpion Centruroides noxius Hoffmann and toxin gamma from the Brazilian scorpion Tityus serrulatus Lutz and Mello have been determined. Cleavage of toxin gamma after Met-6 with CNBr produced the 55-residue peptide 7-61, which maintained the four disulphide bonds but was not toxic to mice at a dose 3 times the lethal dose of native toxin gamma. Pairwise comparison by metric analysis of segment 1-50 of toxin gamma and the corresponding segments from two other South American scorpion toxins, five North American scorpion toxins, nine North African scorpion toxins and one Central Asian scorpion toxin showed that the three Brazilian toxins are intermediate between the North American and North African toxins. This result is consistent with the hypothesis that the South American and African continents were joined by a land connection in the distant past.
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Brogna, Carlo, Simone Cristoni, Mauro Petrillo, Maddalena Querci, Ornella Piazza, and Guy Van den Eede. "Toxin-like peptides in plasma, urine and faecal samples from COVID-19 patients." F1000Research 10 (October 14, 2021): 550. http://dx.doi.org/10.12688/f1000research.54306.2.
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Background: SARS-CoV-2 that causes COVID-19 disease and led to the pandemic currently affecting the world has been broadly investigated. Different studies have been performed to understand the infection mechanism, and the involved human genes, transcripts and proteins. In parallel, numerous clinical extra-pulmonary manifestations co-occurring with COVID-19 disease have been reported and evidence of their severity and persistence is increasing. Whether these manifestations are linked to other disorders co-occurring with SARS-CoV-2 infection, is under discussion. In this work, we report the identification of toxin-like peptides in COVID-19 patients by application of the Liquid Chromatography Surface-Activated Chemical Ionization – Cloud Ion Mobility Mass Spectrometry. Methods: Plasma, urine and faecal samples from COVID-19 patients and control individuals were analysed to study peptidomic toxins’ profiles. Protein precipitation preparation procedure was used for plasma, to remove high molecular weight proteins and efficiently solubilize the peptide fraction; in the case of faeces and urine, direct peptide solubilization was employed. Results: Toxin-like peptides, almost identical to toxic components of venoms from animals, like conotoxins, phospholipases, phosphodiesterases, zinc metal proteinases, and bradykinins, were identified in samples from COVID-19 patients, but not in control samples. Conclusions: The presence of toxin-like peptides could potentially be connected to SARS-CoV-2 infection. Their presence suggests a possible association between COVID-19 disease and the release in the body of (oligo-)peptides almost identical to toxic components of venoms from animals. Their involvement in a large set of heterogeneous extra-pulmonary COVID-19 clinical manifestations, like neurological ones, cannot be excluded. Although the presence of each individual symptom is not selective of the disease, their combination might be related to COVID-19 by the coexistence of the panel of the here detected toxin-like peptides. The presence of these peptides opens new scenarios on the aetiology of the COVID-19 clinical symptoms observed up to now, including neurological manifestations.
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Brogna, Carlo, Simone Cristoni, Mauro Petrillo, Maddalena Querci, Ornella Piazza, and Guy Van den Eede. "Toxin-like peptides in plasma, urine and faecal samples from COVID-19 patients." F1000Research 10 (July 8, 2021): 550. http://dx.doi.org/10.12688/f1000research.54306.1.
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Background: SARS-CoV-2 that causes COVID-19 disease and led to the pandemic currently affecting the world has been broadly investigated. Different studies have been performed to understand the infection mechanism, and the involved human genes, transcripts and proteins. In parallel, numerous clinical extra-pulmonary manifestations co-occurring with COVID-19 disease have been reported and evidence of their severity and persistence is increasing. Whether these manifestations are linked to other disorders co-occurring with SARS-CoV-2 infection, is under discussion. In this work, we report the identification of toxin-like peptides in COVID-19 patients by application of the Liquid Chromatography Surface-Activated Chemical Ionization – Cloud Ion Mobility Mass Spectrometry. Methods: Plasma, urine and faecal samples from COVID-19 patients and control individuals were analysed to study peptidomic toxins’ profiles. Protein precipitation preparation procedure was used for plasma, to remove high molecular weight proteins and efficiently solubilize the peptide fraction; in the case of faeces and urine, direct peptide solubilization was employed. Results: Toxin-like peptides, almost identical to toxic components of venoms from animals, like conotoxins, phospholipases, phosphodiesterases, zinc metal proteinases, and bradykinins, were identified in samples from COVID-19 patients, but not in control samples. Conclusions: The presence of toxin-like peptides could potentially be connected to SARS-CoV-2 infection. Their presence suggests a possible association between COVID-19 disease and the release in the body of (oligo-)peptides almost identical to toxic components of venoms from animals. Their involvement in a large set of heterogeneous extra-pulmonary COVID-19 clinical manifestations, like neurological ones, cannot be excluded. Although the presence of each individual symptom is not selective of the disease, their combination might be related to COVID-19 by the coexistence of the panel of the here detected toxin-like peptides. The presence of these peptides opens new scenarios on the aetiology of the COVID-19 clinical symptoms observed up to now, including neurological manifestations.
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Ma, Menglin, Jihong Li, and Bruce A. McClane. "Structure-Function Analysis of Peptide Signaling in the Clostridium perfringens Agr-Like Quorum Sensing System." Journal of Bacteriology 197, no. 10 (March 16, 2015): 1807–18. http://dx.doi.org/10.1128/jb.02614-14.
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ABSTRACTThe accessory growth regulator (Agr)-like quorum sensing (QS) system ofClostridium perfringenscontrols the production of many toxins, including beta toxin (CPB). We previously showed (J. E. Vidal, M. Ma, J. Saputo, J. Garcia, F. A. Uzal, and B. A. McClane, Mol Microbiol 83:179–194, 2012,http://dx.doi.org/10.1111/j.1365-2958.2011.07925.x) that an 8-amino-acid, AgrD-derived peptide named 8-R upregulates CPB production by this QS system. The current study synthesized a series of small signaling peptides corresponding to sequences within theC. perfringensAgrD polypeptide to investigate theC. perfringensautoinducing peptide (AIP) structure-function relationship. When both linear and cyclic ring forms of these peptides were added toagrBnull mutants of type B strain CN1795 or type C strain CN3685, the 5-amino-acid peptides, whether in a linear or ring (thiolactone or lactone) form, induced better signaling (more CPB production) than peptide 8-R for bothC. perfringensstrains. The 5-mer thiolactone ring peptide induced faster signaling than the 5-mer linear peptide. Strain-related variations in sensing these peptides were detected, with CN3685 sensing the synthetic peptides more strongly than CN1795. Consistent with those synthetic peptide results, Transwell coculture experiments showed that CN3685 exquisitely senses native AIP signals from other isolates (types A, B, C, and D), while CN1795 barely senses even its own AIP. Finally, aC. perfringensAgrD sequence-based peptide with a 6-amino-acid thiolactone ring interfered with CPB production by severalC. perfringensstrains, suggesting potential therapeutic applications. These results indicate that AIP signaling sensitivity and responsiveness vary amongC. perfringensstrains and suggestC. perfringensprefers a 5-mer AIP to initiate Agr signaling.IMPORTANCEClostridium perfringenspossesses an Agr-like quorum sensing (QS) system that regulates virulence, sporulation, and toxin production. The current study used synthetic peptides to identify the structure-function relationship for the signaling peptide that activates this QS system. We found that a 5-mer peptide induces optimal signaling. Unlike other Agr systems, a linear version of this peptide (in addition to thiolactone and lactone versions) could induce signaling. TwoC. perfringensstrains were found to vary in sensitivity to these peptides. We also found that a 6-mer peptide can inhibit toxin production by some strains, suggesting therapeutic applications.
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Shupp, Jeffrey W., Marti Jett, and Carol H. Pontzer. "Identification of a Transcytosis Epitope on Staphylococcal Enterotoxins." Infection and Immunity 70, no. 4 (April 2002): 2178–86. http://dx.doi.org/10.1128/iai.70.4.2178-2186.2002.
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ABSTRACT Staphylococcal enterotoxins (SE) are exoproteins produced by Staphylococcus aureus that act as superantigens and have been implicated as a leading cause of food-borne disease and toxic shock. Little is known about how these molecules penetrate the gut lining and gain access to both local and systemic immune tissues. To model movement in vitro of staphylococcal enterotoxins, we have employed a monolayer system composed of crypt-like human colonic T-84 cells. SEB and SEA showed comparable dose-dependent transcytosis in vitro, while toxic shock syndrome toxin (TSST-1) exhibited increased movement at lower doses. Synthetic peptides corresponding to specific regions of the SEB molecule were tested in vitro to identify the domain of the protein involved in the transcytosis of SE. A toxin peptide of particular interest contains the amino acid sequence KKKVTAQELD, which is highly conserved across all SE. At a toxin-to-peptide ratio of 1:10, movement of SEB across the monolayers was reduced by 85%. Antisera made against the SEB peptide recognized native SEB and also inhibited SEB transcytosis. Finally, the conserved 10-amino-acid peptide inhibited transcytosis of multiple staphylococcal enterotoxins, SEA, SEE, and TSST-1. These data demonstrate that this region of the staphylococcal enterotoxins plays a distinct role in toxin movement across epithelial cells. It has implications for the prevention of staphylococcal enterotoxin-mediated disease by design of a peptide vaccine that could reduce systemic exposure to oral or inhaled superantigens. Since the sequence identified is highly conserved, it allows for a single epitope blocking the transcytosis of multiple SE.
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Wu, Xiangyue, Yan Chen, Hao Liu, Xiangjin Kong, Xinyao Liang, Yu Zhang, Cheng Tang, and Zhonghua Liu. "The Molecular Composition of Peptide Toxins in the Venom of Spider Lycosa coelestis as Revealed by cDNA Library and Transcriptomic Sequencing." Toxins 15, no. 2 (February 10, 2023): 143. http://dx.doi.org/10.3390/toxins15020143.
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In the so-called “struggle for existence” competition, the venomous animals developed a smart and effective strategy, envenomation, for predation and defense. Biochemical analysis revealed that animal venoms are chemical pools of proteinase, peptide toxins, and small organic molecules with various biological activities. Of them, peptide toxins are of great molecular diversity and possess the capacity to modulate the activity of ion channels, the second largest group of drug targets expressed on the cell membrane, which makes them a rich resource for developing peptide drug pioneers. The spider Lycosa coelestis (L. coelestis) commonly found in farmland in China is a dominant natural enemy of agricultural pests; however, its venom composition and activity were never explored. Herein, we conducted cDNA library and transcriptomic sequencing of the venom gland of L. coelestis, which identified 1131 high-quality expressed sequence tags (ESTs), grouped into three categories denoted as toxin-like ESTs (597, 52.79%), cellular component ESTs (357, 31.56%), and non-matched ESTs (177, 15.65%). These toxin-like ESTs encode 98 non-reductant toxins, which are artificially divided into 11 families based on their sequence homology and cysteine frameworks (2–14 cysteines forming 1–7 disulfide bonds to stabilize the toxin structure). Furthermore, RP-HPLC purification combined with off-line MALDI-TOF analysis have detected 147 different peptides physically existing in the venom of L. coelestis. Electrophysiology analysis confirmed that the venom preferably inhibits the voltage-gated calcium channels in rat dorsal root ganglion neurons. Altogether, the present study has added a great lot of new members to the spider toxin superfamily and built the foundation for characterizing novel active peptides in the L. coelestis venom.
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Léonetti, M., L. Pillet, B. Maillère, H. Lamthanh, P. Frachon, J. Couderc, and A. Ménez. "Immunization with a peptide having both T cell and conformationally restricted B cell epitopes elicits neutralizing antisera against a snake neurotoxin." Journal of Immunology 145, no. 12 (December 15, 1990): 4214–21. http://dx.doi.org/10.4049/jimmunol.145.12.4214.
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Abstract We have synthesized a free peptide capable of eliciting antibodies that neutralize toxin alpha from Naja nigricollis, a protein that binds specifically to the acetylcholine nicotinic receptor. Of the five tested fragments that encompassed the whole toxin sequence, only fragment 24-41 stimulated T cells from BALB/c mice primed with the whole toxin and conversely, only T cells from mice primed with fragment 24-41 could be stimulated by both the toxin and priming peptide. No other peptides had such properties, indicating that only fragment 24-41 possessed T determinant(s) in BALB/c mice (H-2d haplotype). In agreement with the current view that B cell proliferation requires specific T cell stimulation, only fragment 24-41 elicited an antibody response. However, the antipeptide antisera failed to bind to the native toxin and thereby to neutralize it. Instead, it recognized an unfolded form of the toxin. The peptide 24-41 was then made cyclic. A circular dichroism analysis revealed that, in organic solvent, this peptide had a tendency to adopt a beta-sheet structure, as in the folded toxin, whereas the linear peptide adopted an helical structure. The cyclic peptide not only remained T stimulating but elicited antisera that recognized and neutralized the native toxin. Furthermore, the antisera cross-reacted with several toxin variants. Our data show, therefore, that it is possible to give an appropriate B cell specificity directly to a T cell-stimulating peptide, an approach that may be of value for the design of synthetic vaccines.
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Shah, Binita, Dan Sindhikara, Ken Borrelli, and Abba E. Leffler. "Water Thermodynamics of Peptide Toxin Binding Sites on Ion Channels." Toxins 12, no. 10 (October 12, 2020): 652. http://dx.doi.org/10.3390/toxins12100652.
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Peptide toxins isolated from venomous creatures, long prized as research tools due to their innate potency for ion channels, are emerging as drugs as well. However, it remains challenging to understand why peptide toxins bind with high potency to ion channels, to identify residues that are key for activity, and to improve their affinities via mutagenesis. We use WaterMap, a molecular dynamics simulation-based method, to gain computational insight into these three questions by calculating the locations and thermodynamic properties of water molecules in the peptide toxin binding sites of five ion channels. These include an acid-sensing ion channel, voltage-gated potassium channel, sodium channel in activated and deactivated states, transient-receptor potential channel, and a nicotinic receptor whose structures were recently determined by crystallography and cryo-electron microscopy (cryo-EM). All channels had water sites in the peptide toxin binding site, and an average of 75% of these sites were stable (low-energy), and 25% were unstable (medium or high energy). For the sodium channel, more unstable water sites were present in the deactivated state structure than the activated. Additionally, for each channel, unstable water sites coincided with the positions of peptide toxin residues that previous mutagenesis experiments had shown were important for activity. Finally, for the sodium channel in the deactivated state, unstable water sites were present in the peptide toxin binding pocket but did not overlap with the peptide toxin, suggesting that future experimental efforts could focus on targeting these sites to optimize potency.
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Tsutsuki, Kazue, Miho Watanabe-Takahashi, Yasuaki Takenaka, Eiji Kita, and Kiyotaka Nishikawa. "Identification of a Peptide-Based Neutralizer That Potently Inhibits Both Shiga Toxins 1 and 2 by Targeting Specific Receptor-Binding Regions." Infection and Immunity 81, no. 6 (April 1, 2013): 2133–38. http://dx.doi.org/10.1128/iai.01256-12.
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ABSTRACTShiga toxin (Stx) is a major virulence factor of enterohemorrhagicEscherichia colithat occasionally causes fatal systemic complications. We recently developed a tetravalent peptide (PPP-tet) that neutralizes the cytotoxicity of Stx2 using a multivalent peptide library approach. In this study, we used this technique to identify a series of tetravalent peptides that bound to Stx1, another major Stx family member, with high affinity by targeting one receptor-binding site of the B subunit. One peptide, MMA-tet, markedly inhibited Stx1 and Stx2 cytotoxicity with greater potency than PPP-tet. After forming a complex with Stx1 through its specific receptor-binding region, MMA-tet did not affect vesicular transport of the toxin to the endoplasmic reticulum but substantially rescued inhibition of the protein synthesis induced by Stx1. Oral application of MMA-tet protected mice from a fatal dose of anE. coliO157:H7 strain producing both toxins. MMA-tet may be a promising therapeutic agent against the infection.
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Rahman, Khalidur, Mohd Amir F. Abdullah, Suresh Ambati, Milton D. Taylor, and Michael J. Adang. "Differential Protection of Cry1Fa Toxin against Spodoptera frugiperda Larval Gut Proteases by Cadherin Orthologs Correlates with Increased Synergism." Applied and Environmental Microbiology 78, no. 2 (November 11, 2011): 354–62. http://dx.doi.org/10.1128/aem.06212-11.
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ABSTRACTThe Cry proteins produced byBacillus thuringiensis(Bt) are the most widely used biopesticides effective against a range of crop pests and disease vectors. Like chemical pesticides, development of resistance is the primary threat to the long-term efficacy of Bt toxins. Recently discovered cadherin-based Bt Cry synergists showed the potential to augment resistance management by improving efficacy of Cry toxins. However, the mode of action of Bt Cry synergists is thus far unclear. Here we elucidate the mechanism of cadherin-based Cry toxin synergism utilizing two cadherin peptides,Spodoptera frugiperdaCad (SfCad) andManduca sextaCad (MsCad), which differentially enhance Cry1Fa toxicity toSpodoptera frugiperdaneonates. We show that differential SfCad- and MsCad-mediated protection of Cry1Fa toxin in theSpodoptera frugiperdamidgut correlates with differential Cry1Fa toxicity enhancement. Both peptides exhibited high affinity for Cry1Fa toxin and an increased rate of Cry1Fa-induced pore formation inS. frugiperda. However, only SfCad bound theS. frugiperdabrush border membrane vesicle and more effectively prolonged the stability of Cry1Fa toxin in the gut, explaining higher Cry1Fa enhancement by this peptide. This study shows that cadherin fragments may enhanceB. thuringiensistoxicity by at least two different mechanisms or a combination thereof: (i) protection of Cry toxin from protease degradation in the insect midgut and (ii) enhancement of pore-forming ability of Cry toxin.
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Fainzilber, Michael, Iris Napchi, Dalia Gordon, and Eliahu Zlotkin. "Marine warning via peptide toxin." Nature 369, no. 6477 (May 1994): 192–93. http://dx.doi.org/10.1038/369192a0.
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Shanmugavelu, M., F. Rajamohan, M. Kathirvel, G. Elangovan, D. H. Dean, and Kunthala Jayaraman. "Functional Complementation of Nontoxic Mutant Binary Toxins of Bacillus sphaericus 1593M Generated by Site-Directed Mutagenesis." Applied and Environmental Microbiology 64, no. 2 (February 1, 1998): 756–59. http://dx.doi.org/10.1128/aem.64.2.756-759.1998.
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ABSTRACT Alanine residues were substituted by site-directed mutagenesis at selected sites of the N- and C-terminal regions of the binary toxin (51- and 42-kDa peptides) of B. sphaericus 1593M, and the mutant toxins were cloned and expressed in Escherichia coli. Bioassays with mosquito larvae, using binary toxins derived from individual mutants, showed that the substitution of alanine at some sites in both the 51-kDa and the 42-kDa peptides resulted in a total loss of activity. Surprisingly, after mixing two nontoxic derivatives of the same peptide, i.e., one mutated at the N-terminal end and the other mutated at the C-terminal end of either the 51-kDa or the 42-kDa peptide, the toxicity was restored. This result indicates that the altered binary toxins can functionally complement each other by forming oligomers.
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Stenmark, H., J. O. Moskaug, I. H. Madshus, K. Sandvig, and S. Olsnes. "Peptides fused to the amino-terminal end of diphtheria toxin are translocated to the cytosol." Journal of Cell Biology 113, no. 5 (June 1, 1991): 1025–32. http://dx.doi.org/10.1083/jcb.113.5.1025.
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Diphtheria toxin belongs to a group of toxic proteins that enter the cytosol of animal cells. We have here investigated the effect of NH2-terminal extensions of diphtheria toxin on its ability to become translocated to the cytosol. DNA fragments encoding peptides of 12-30 amino acids were fused by recombinant DNA technology to the 5'-end of the gene for a mutant toxin. The resulting DNA constructs were transcribed and translated in vitro. The translation products were bound to cells and then exposed to low pH to induce translocation across the cell membrane. Under these conditions all of the oligopeptides tested, including three viral peptides and the leader peptide of diphtheria toxin, were translocated to the cytosol along with the enzymatic part (A-fragment) of the toxin. Neither hydrophobic nor highly charged sequences blocked translocation. The results are compatible with a model in which the COOH-terminus of the A-fragment first crosses the membrane, whereas the NH2-terminal region follows behind. The possibility of using nontoxic variants of diphtheria toxin as vectors to introduce peptides into the cytosol to elicit MHC class I-restricted immune response and clonal expansion of the relevant CD8+ cytotoxic T lymphocytes is discussed.
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Visvanathan, Kumar, Alain Charles, Jason Bannan, Pavel Pugach, Khosrow Kashfi, and John B. Zabriskie. "Inhibition of Bacterial Superantigens by Peptides and Antibodies." Infection and Immunity 69, no. 2 (February 1, 2001): 875–84. http://dx.doi.org/10.1128/iai.69.2.875-884.2001.
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ABSTRACT The pyrogenic exotoxins of group A streptococci and staphylococcal enterotoxins are a family of structurally related superantigens with similar biological activity. Two distinct areas have been identified which have a highly conserved amino acid homology in all of the toxin families. A number of peptides were constructed from these regions, some of which were concatenated and polymerized to enhance their immunogenicity in animals. Antibodies prepared against these polymerized peptides were used to serologically identify the majority of the superantigen toxins, block the biological activities of the superantigens, and protect an experimental animal model against shock. In addition certain peptides were able per se to block up to 90% of the proliferative responses induced by the toxins. The peptide also proved protective in a septic shock model in mice. Binding experiments indicate that the peptide binds tightly to the major histocompatibility complex class II molecule, thus preventing binding and hence activation of the superantigen. The selective and rapid binding of the peptide to the major histocompatibility complex class II molecule may lead to a novel therapeutic modality in treatment of superantigen-mediated diseases.
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Duracova, Miloslava, Jana Klimentova, Alena Myslivcova Fucikova, Lenka Zidkova, Valeria Sheshko, Helena Rehulkova, Jiri Dresler, and Zuzana Krocova. "Targeted Mass Spectrometry Analysis of Clostridium perfringens Toxins." Toxins 11, no. 3 (March 23, 2019): 177. http://dx.doi.org/10.3390/toxins11030177.
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Targeted proteomics recently proved to be a technique for the detection and absolute quantification of proteins not easily accessible to classical bottom-up approaches. Due to this, it has been considered as a high fidelity tool to detect potential warfare agents in wide spread kinds of biological and environmental matrices. Clostridium perfringens toxins are considered to be potential biological weapons, especially the epsilon toxin which belongs to a group of the most powerful bacterial toxins. Here, the development of a target mass spectrometry method for the detection of C. perfringens protein toxins (alpha, beta, beta2, epsilon, iota) is described. A high-resolution mass spectrometer with a quadrupole-Orbitrap system operating in target acquisition mode (parallel reaction monitoring) was utilized. Because of the lack of commercial protein toxin standards recombinant toxins were prepared within Escherichia coli. The analysis was performed using proteotypic peptides as the target compounds together with their isotopically labeled synthetic analogues as internal standards. Calibration curves were calculated for each peptide in concentrations ranging from 0.635 to 1101 fmol/μL. Limits of detection and quantification were determined for each peptide in blank matrices.
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Leffler, Abba E., Alexander Kuryatov, Henry A. Zebroski, Susan R. Powell, Petr Filipenko, Adel K. Hussein, Juliette Gorson, et al. "Discovery of peptide ligands through docking and virtual screening at nicotinic acetylcholine receptor homology models." Proceedings of the National Academy of Sciences 114, no. 38 (September 5, 2017): E8100—E8109. http://dx.doi.org/10.1073/pnas.1703952114.
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Venom peptide toxins such as conotoxins play a critical role in the characterization of nicotinic acetylcholine receptor (nAChR) structure and function and have potential as nervous system therapeutics as well. However, the lack of solved structures of conotoxins bound to nAChRs and the large size of these peptides are barriers to their computational docking and design. We addressed these challenges in the context of the α4β2 nAChR, a widespread ligand-gated ion channel in the brain and a target for nicotine addiction therapy, and the 19-residue conotoxin α-GID that antagonizes it. We developed a docking algorithm, ToxDock, which used ensemble-docking and extensive conformational sampling to dock α-GID and its analogs to an α4β2 nAChR homology model. Experimental testing demonstrated that a virtual screen with ToxDock correctly identified three bioactive α-GID mutants (α-GID[A10V], α-GID[V13I], and α-GID[V13Y]) and one inactive variant (α-GID[A10Q]). Two mutants, α-GID[A10V] and α-GID[V13Y], had substantially reduced potency at the human α7 nAChR relative to α-GID, a desirable feature for α-GID analogs. The general usefulness of the docking algorithm was highlighted by redocking of peptide toxins to two ion channels and a binding protein in which the peptide toxins successfully reverted back to near-native crystallographic poses after being perturbed. Our results demonstrate that ToxDock can overcome two fundamental challenges of docking large toxin peptides to ion channel homology models, as exemplified by the α-GID:α4β2 nAChR complex, and is extendable to other toxin peptides and ion channels. ToxDock is freely available atrosie.rosettacommons.org/tox_dock.
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Kalb, Suzanne R., Jakub Baudys, Christina Egan, Theresa J. Smith, Leonard A. Smith, James L. Pirkle, and John R. Barr. "Different Substrate Recognition Requirements for Cleavage of Synaptobrevin-2 byClostridium baratiiandClostridium botulinumType F Neurotoxins." Applied and Environmental Microbiology 77, no. 4 (December 17, 2010): 1301–8. http://dx.doi.org/10.1128/aem.01662-10.
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ABSTRACTBotulinum neurotoxins (BoNTs) cause botulism, which can be fatal if it is untreated. BoNTs cleave proteins necessary for nerve transmission, resulting in paralysis. Thein vivoprotein target has been reported for all seven serotypes of BoNT, i.e., serotypes A to G. Knowledge of the cleavage sites has led to the development of several assays to detect BoNT based on its ability to cleave a peptide substrate derived from itsin vivoprotein target. Most serotypes of BoNT can be subdivided into subtypes, and previously, we demonstrated that three of the currently known subtypes of BoNT/F cleave a peptide substrate, a shortened version of synaptobrevin-2, between Q58 and K59. However, our research indicated thatClostridium baratiitype F toxin did not cleave this peptide. In this study, we detail experiments demonstrating thatClostridium baratiitype F toxin cleaves recombinant synaptobrevin-2 in the same location as that cleaved by proteolytic F toxin. In addition, we demonstrate thatClostridium baratiitype F toxin can cleave a peptide substrate based on the sequence of synaptobrevin-2. This peptide substrate is an N-terminal extension of the original peptide substrate used for detection of other BoNT/F toxins and can be used to detect four of the currently known BoNT/F subtypes by mass spectrometry.
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De Cena, Gabrielle Lupeti, Bruna Vitória Scavassa, and Katia Conceição. "In Silico Prediction of Anti-Infective and Cell-Penetrating Peptides from Thalassophryne nattereri Natterin Toxins." Pharmaceuticals 15, no. 9 (September 13, 2022): 1141. http://dx.doi.org/10.3390/ph15091141.
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The therapeutic potential of venom-derived peptides, such as bioactive peptides (BAPs), is determined by specificity, stability, and pharmacokinetics properties. BAPs, including anti-infective or antimicrobial peptides (AMPs) and cell-penetrating peptides (CPPs), share several physicochemical characteristics and are potential alternatives to antibiotic-based therapies and drug delivery systems, respectively. This study used in silico methods to predict AMPs and CPPs derived from natterins from the venomous fish Thalassophryne nattereri. Fifty-seven BAPs (19 AMPs, 8 CPPs, and 30 AMPs/CPPs) were identified using the web servers CAMP, AMPA, AmpGram, C2Pred, and CellPPD. The physicochemical properties were analyzed using ProtParam, PepCalc, and DispHred tools. The membrane-binding potential and cellular location of each peptide were analyzed using the Boman index by APD3, and TMHMM web servers. All CPPs and two AMPs showed high membrane-binding potential. Fifty-four peptides were located in the plasma membrane. Peptide immunogenicity, toxicity, allergenicity, and ADMET parameters were evaluated using several web servers. Sixteen antiviral peptides and 37 anticancer peptides were predicted using the web servers Meta-iAVP and ACPred. Secondary structures and helical wheel projections were predicted using the PEP-FOLD3 and Heliquest web servers. Fifteen peptides are potential lead compounds and were selected to be further synthesized and tested experimentally in vitro to validate the in silico screening. The use of computer-aided design for predicting peptide structure and activity is fast and cost-effective and facilitates the design of potent therapeutic peptides. The results demonstrate that toxins form a natural biotechnological platform in drug discovery, and the presence of CPP and AMP sequences in toxin families opens new possibilities in toxin biochemistry research.
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BECERRIL, Baltazar, Miguel CORONA, Fredy I. V. CORONAS, Fernando ZAMUDIO, Emma S. CALDERONARANDA, Paul L. FLETCHER, Brian M. MARTIN, and Lourival D. POSSANI. "Toxic peptides and genes encoding toxin γ of the Brazilian scorpions Tityus bahiensis and Tityus stigmurus." Biochemical Journal 313, no. 3 (February 1, 1996): 753–60. http://dx.doi.org/10.1042/bj3130753.
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Seven toxic peptides from the venom of Tityus bahiensis and Tityus stigmurus were isolated and sequenced, five of them to completion. The most abundant peptide from each of these two species of scorpion was 95% identical with that of toxin γ from the venom of Tityus serrulatus. They were consequently named γ-b and γ-st respectively. The genes encoding these new γ-like peptides were cloned and sequenced by utilizing oligonucleotides synthesized according to known cDNA sequences of toxin γ, and amplified by PCR on templates of DNA purified from both T. bahiensis and T. stigmurus. They contain an intron of approx. 470 bp. Possible mechanisms of processing and expressing these peptides are discussed, in view of the fact that glycine is the first residue of the N-terminal sequence of T. stigmurus, whereas lysine is the residue at position 1 of toxin γ from T. serrulatus and T. bahiensis. In addition, chemical characterization of the less abundant toxic peptides showed the presence of at least four distinct families of peptides in all three species of the genus Tityus studied. There is a large degree of similarity among peptides from different venoms of the same family. By using specific horse and rabbit antisera, the venoms of T. bahiensis, T. serrulatus and T. stigmurus were compared. They showed an extended degree of cross-reactivity. Thus these three species of scorpion have similar toxic components, the genes of which are similarly organized, processed and expressed.
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Kuhn-Nentwig, Lucia, Nicolas Langenegger, Manfred Heller, Dominique Koua, and Wolfgang Nentwig. "The Dual Prey-Inactivation Strategy of Spiders—In-Depth Venomic Analysis of Cupiennius salei." Toxins 11, no. 3 (March 19, 2019): 167. http://dx.doi.org/10.3390/toxins11030167.
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Most knowledge of spider venom concerns neurotoxins acting on ion channels, whereas proteins and their significance for the envenomation process are neglected. The here presented comprehensive analysis of the venom gland transcriptome and proteome of Cupiennius salei focusses on proteins and cysteine-containing peptides and offers new insight into the structure and function of spider venom, here described as the dual prey-inactivation strategy. After venom injection, many enzymes and proteins, dominated by α-amylase, angiotensin-converting enzyme, and cysteine-rich secretory proteins, interact with main metabolic pathways, leading to a major disturbance of the cellular homeostasis. Hyaluronidase and cytolytic peptides destroy tissue and membranes, thus supporting the spread of other venom compounds. We detected 81 transcripts of neurotoxins from 13 peptide families, whereof two families comprise 93.7% of all cysteine-containing peptides. This raises the question of the importance of the other low-expressed peptide families. The identification of a venom gland-specific defensin-like peptide and an aga-toxin-like peptide in the hemocytes offers an important clue on the recruitment and neofunctionalization of body proteins and peptides as the origin of toxins.
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Pennington, M. W., V. M. Mahnir, P. Baur, C. T. McVaugh, D. Behm, and W. R. Kem. "The effect of truncation on shk toxin:• elimination of the amino-carboxyl terminal (3-35) disulfide linkage stabilizing the amino and carboxyl terminal segments." Protein & Peptide Letters 4, no. 4 (August 1997): 237–42. http://dx.doi.org/10.2174/092986650404221017121816.
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Abstract: We have synthesized two truncated analogs of ShK toxin which contain the main residues comprising the binding surface of the toxin. In both of these analogs, the disulfide bond which links the N and C terminal Cys residues has been eliminated. The remaining two disulfide bonds (Cys12-Cys28, Cysl 7-Cys32) have been retained in one analog and the other analog contains only the Cys17-Cys32 linkage. The CD spectrum of the bicyclic peptide appears to have a small amount of the helical structure whereas the monocyclic peptide spectrum appears to be disordered. The activity of the bicyclic and monocyclic peptides were respectively reduced by 1360- and >3000-fold relative to wild type ShK toxin.
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Otsuka, Ishikawa, Takahashi, and Masuda. "A Short Peptide Derived from the ZorO Toxin Functions as an Effective Antimicrobial." Toxins 11, no. 7 (July 4, 2019): 392. http://dx.doi.org/10.3390/toxins11070392.
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Antimicrobial peptides are potential molecules for the development of novel antibiotic agents. The ZorO toxin of a type I toxin–antitoxin system in Escherichia coli O157:H7 is composed of 29 amino acids and its endogenous expression inhibits E. coli growth. However, little is known about its inhibitory mechanism. In this study, we demonstrate that the ZorO localized in the inner membrane affects the plasma membrane integrity and potential when expressed in E. coli cells, which triggers the production of cytotoxic hydroxyl radicals. We further show that five internal amino acids (Ala–Leu–Leu–Arg–Leu; ALLRL) of ZorO are necessary for its toxicity. This result prompted us to address the potential of the synthetic ALLRL peptide as an antimicrobial. Exogenously-added ALLRL peptide to Gram-positive bacteria, Staphylococcus aureus and Bacillus subtilis, and a fungus, Candida albicans, trigger cell membrane damage and exhibit growth defect, while having no effect on Gram-negative bacterium, E. coli. The ALLRL peptide retains its activity under the physiological salt concentrations, which is in contrast to natural antimicrobial peptides. Importantly, this peptide has no toxicity against mammalian cells. Taken together, an effective and short peptide, ALLRL, would be an attractive antimicrobial to Gram-positive bacteria and C. albicans.
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Wen, R., G. A. Cole, S. Surman, M. A. Blackman, and D. L. Woodland. "Major histocompatibility complex class II-associated peptides control the presentation of bacterial superantigens to T cells." Journal of Experimental Medicine 183, no. 3 (March 1, 1996): 1083–92. http://dx.doi.org/10.1084/jem.183.3.1083.
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Recent studies have shown that only a subset of major histocompatibility complex (MHC) class II molecules are able to present bacterial superantigens to T cells, leading to the suggestion that class-II associated peptides may influence superantigen presentation. Here, we have assessed the potential role of peptides on superantigen presentation by (a) analyzing the ability of superantigens to block peptide-specific T cell responses and (b) analyzing the ability of individual peptides to promote superantigen presentation on I-Ab-expressing T2 cells that have a quantitative defect in antigen processing. A series of peptides is described that specifically promote either toxic shock syndrome toxin (TSST) 1 or staphylococcal enterotoxin A (SEA) presentation. Whereas some peptides promoted the presentation of TSST-1 (almost 5,000-fold in the case of one peptide), other peptides promoted the presentation of SEA. These data demonstrate that MHC class II-associated peptides differentially influence the presentation of bacterial superantigens to T cells.
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Park, Youngjin, Mohd Amir F. Abdullah, Milton D. Taylor, Khalidur Rahman, and Michael J. Adang. "Enhancement of Bacillus thuringiensis Cry3Aa and Cry3Bb Toxicities to Coleopteran Larvae by a Toxin-Binding Fragment of an Insect Cadherin." Applied and Environmental Microbiology 75, no. 10 (March 27, 2009): 3086–92. http://dx.doi.org/10.1128/aem.00268-09.
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ABSTRACT The Cry3Aa and Cry3Bb insecticidal proteins of Bacillus thuringiensis are used in biopesticides and transgenic crops to control larvae of leaf-feeding beetles and rootworms. Cadherins localized in the midgut epithelium are identified as receptors for Cry toxins in lepidopteran and dipteran larvae. Previously, we discovered that a peptide of a toxin-binding cadherin expressed in Escherichia coli functions as a synergist for Cry1A toxicity against lepidopteran larvae and Cry4 toxicity against dipteran larvae. Here we report that the fragment containing the three most C-terminal cadherin repeats (CR) from the cadherin of the western corn rootworm binds toxin and enhances Cry3 toxicity to larvae of naturally susceptible species. The cadherin fragment (CR8 to CR10 [CR8-10]) of western corn rootworm Diabrotica virgifera virgifera was expressed in E. coli as an inclusion body. By an enzyme-linked immunosorbent microplate assay, we demonstrated that the CR8-10 peptide binds α-chymotrypsin-treated Cry3Aa and Cry3Bb toxins at high affinity (11.8 nM and 1.4 nM, respectively). Coleopteran larvae ingesting CR8-10 inclusions had increased susceptibility to Cry3Aa or Cry3Bb toxin. The Cry3 toxin-enhancing effect of CR8-10 was demonstrated for Colorado potato beetle Leptinotarsa decemlineata, southern corn rootworm Diabrotica undecimpunctata howardi, and western corn rootworm. The extent of Cry3 toxin enhancement, which ranged from 3- to 13-fold, may have practical applications for insect control. Cry3-containing biopesticides that include a cadherin fragment could be more efficacious. And Bt corn (i.e., corn treated with B. thuringiensis to make it resistant to pests) coexpressing Cry3Bb and CR8-10 could increase the functional dose level of the insect toxic activity, reducing the overall resistance risk.
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Morozov, Vladimir, Carlos H. M. Rodrigues, and David B. Ascher. "CSM-Toxin: A Web-Server for Predicting Protein Toxicity." Pharmaceutics 15, no. 2 (January 28, 2023): 431. http://dx.doi.org/10.3390/pharmaceutics15020431.
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Biologics are one of the most rapidly expanding classes of therapeutics, but can be associated with a range of toxic properties. In small-molecule drug development, early identification of potential toxicity led to a significant reduction in clinical trial failures, however we currently lack robust qualitative rules or predictive tools for peptide- and protein-based biologics. To address this, we have manually curated the largest set of high-quality experimental data on peptide and protein toxicities, and developed CSM-Toxin, a novel in-silico protein toxicity classifier, which relies solely on the protein primary sequence. Our approach encodes the protein sequence information using a deep learning natural languages model to understand “biological” language, where residues are treated as words and protein sequences as sentences. The CSM-Toxin was able to accurately identify peptides and proteins with potential toxicity, achieving an MCC of up to 0.66 across both cross-validation and multiple non-redundant blind tests, outperforming other methods and highlighting the robust and generalisable performance of our model. We strongly believe the CSM-Toxin will serve as a valuable platform to minimise potential toxicity in the biologic development pipeline. Our method is freely available as an easy-to-use webserver.
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Fischer, Peter M., and Merlin E. H. Howden. "Synthetic peptide antigens of tetanus toxin." Molecular Immunology 31, no. 15 (October 1994): 1141–48. http://dx.doi.org/10.1016/0161-5890(94)90028-0.
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Liang, Long-Hui, Chang-Cai Liu, Bo Chen, Long Yan, Hui-Lan Yu, Yang Yang, Ji-Na Wu, Xiao-Sen Li, and Shi-Lei Liu. "LC-HRMS Screening and Identification of Novel Peptide Markers of Ricin Based on Multiple Protease Digestion Strategies." Toxins 11, no. 7 (July 5, 2019): 393. http://dx.doi.org/10.3390/toxins11070393.
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Both ricin and R. communis agglutinin (RCA120), belonging to the type II ribosome-inactivating proteins (RIPs-Ⅱ), are derived from the seeds of the castor bean plant. They share very similar amino acid sequences, but ricin is much more toxic than RCA120. It is urgently necessary to distinguish ricin and RCA120 in response to public safety. Currently, mass spectrometric assays are well established for unambiguous identification of ricin by accurate analysis of differentiated amino acid residues after trypsin digestion. However, diagnostic peptides are relatively limited for unambiguous identification of trace ricin, especially in complex matrices. Here, we demonstrate a digestion strategy of multiple proteinases to produce novel peptide markers for unambiguous identification of ricin. Liquid chromatography-high resolution MS (LC-HRMS) was used to verify the resulting peptides, among which only the peptides with uniqueness and good MS response were selected as peptide markers. Seven novel peptide markers were obtained from tandem digestion of trypsin and endoproteinase Glu-C in PBS buffer. From the chymotrypsin digestion under reduction and non-reduction conditions, eight and seven novel peptides were selected respectively. Using pepsin under pH 1~2 and proteinase K digestion, six and five peptides were selected as novel peptide markers. In conclusion, the obtained novel peptides from the established digestion methods can be recommended for the unambiguous identification of ricin during the investigation of illegal use of the toxin.
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Melnik, Lilia I., and Robert F. Garry. "Enterotoxigenic Escherichia coli Heat-Stable Toxin and Ebola Virus Delta Peptide: Similarities and Differences." Pathogens 11, no. 2 (January 27, 2022): 170. http://dx.doi.org/10.3390/pathogens11020170.
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Enterotoxigenic Escherichia coli (ETEC) STb toxin exhibits striking structural similarity to Ebola virus (EBOV) delta peptide. Both ETEC and EBOV delta peptide are enterotoxins. Comparison of the structural and functional similarities and differences of these two toxins illuminates features that are important in induction of pathogenesis by a bacterial and viral pathogen.
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Nicolas, Zoukimian, Bosmans, Montnach, Diochot, Cuypers, De Waard, et al. "Chemical Synthesis, Proper Folding, Nav Channel Selectivity Profile and Analgesic Properties of the Spider Peptide Phlotoxin 1." Toxins 11, no. 6 (June 21, 2019): 367. http://dx.doi.org/10.3390/toxins11060367.
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Phlotoxin-1 (PhlTx1) is a peptide previously identified in tarantula venom (Phlogius species) that belongs to the inhibitory cysteine-knot (ICK) toxin family. Like many ICK-based spider toxins, the synthesis of PhlTx1 appears particularly challenging, mostly for obtaining appropriate folding and concomitant suitable disulfide bridge formation. Herein, we describe a procedure for the chemical synthesis and the directed sequential disulfide bridge formation of PhlTx1 that allows for a straightforward production of this challenging peptide. We also performed extensive functional testing of PhlTx1 on 31 ion channel types and identified the voltage-gated sodium (Nav) channel Nav1.7 as the main target of this toxin. Moreover, we compared PhlTx1 activity to 10 other spider toxin activities on an automated patch-clamp system with Chinese Hamster Ovary (CHO) cells expressing human Nav1.7. Performing these analyses in reproducible conditions allowed for classification according to the potency of the best natural Nav1.7 peptide blockers. Finally, subsequent in vivo testing revealed that intrathecal injection of PhlTx1 reduces the response of mice to formalin in both the acute pain and inflammation phase without signs of neurotoxicity. PhlTx1 is thus an interesting toxin to investigate Nav1.7 involvement in cellular excitability and pain.
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MACAULAY, S. Lance, Dean R. HEWISH, Keith H. GOUGH, Violet STOICHEVSKA, Susan F. MACPHERSON, Mittur JAGADISH, and Colin W. WARD. "Functional studies in 3T3L1 cells support a role for SNARE proteins in insulin stimulation of GLUT4 translocation." Biochemical Journal 324, no. 1 (May 15, 1997): 217–24. http://dx.doi.org/10.1042/bj3240217.
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Insulin stimulation of glucose transport in the major insulin-responsive tissues results predominantly from the translocation to the cell surface of a particular glucose transporter isoform, GLUT4, residing normally under basal conditions in intracellular vesicular structures. Recent studies have identified the presence of vesicle-associated membrane protein (VAMP) 2, a protein involved in vesicular trafficking in secretory cell types, in the vesicles of insulin-sensitive cells that contain GLUT4. The plasma membranes of insulin-responsive cells have also been shown to contain syntaxin 4 and the 25 kDa synaptosome-associated protein (SNAP-25), two proteins that form a complex with VAMP 2. The potential functional involvement of VAMP 2, SNAP-25 and syntaxin 4 in the trafficking of GLUT4 was assessed in the present study by determining the effect on GLUT4 translocation of microinjection of toxins that specifically cleave VAMPs or SNAP-25, or microinjection of specific peptides from VAMP 2 and syntaxin 4. Microinjection of tetanus toxin light chain or botulinum D toxin light chain resulted in an 80 and 61% inhibition respectively of insulin stimulation of GLUT4 translocation in 3T3L1 cells assessed using the plasma-membrane lawn assay. Botulinum A toxin light chain, which cleaves SNAP-25, was without effect. Microinjection of an N-terminal VAMP 2 peptide (residues 1–26) inhibited insulin stimulation of GLUT4 translocation by 54%. A syntaxin 4 peptide (residues 106–122) inhibited insulin stimulation of GLUT4 translocation by 40% whereas a syntaxin 1c peptide (residues 226–260) was without effect. These data taken together strongly suggest a role for VAMP 2 in GLUT4 trafficking and also for syntaxin 4. They further indicate that the isoforms of SNAP-25 isolated to date that are sensitive to cleavage by botulinum A toxin light chain do not appear to be involved in GLUT4 translocation.
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Maslanka, Jeffrey, Joshua E. Denny, MD Z. Alam, Mohamad-Gabriel Alameh, Joseph P. Zackular, and Michael C. Abt. "C. difficileinfection induces toxin A specific responses." Journal of Immunology 210, no. 1_Supplement (May 1, 2023): 218.25. http://dx.doi.org/10.4049/jimmunol.210.supp.218.25.
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Abstract The nosocomial pathogen Clostridioides difficile colonizes the gastrointestinal tract of patients following microbiome disruption and secretes two major virulence factors toxin A (TcdA) and toxin B (TcdB). Approximately 25% of patients infected with C. difficile experience recurrent infection, and the rate of recurrence increases with each subsequent infection. The quality and protective capacity of the adaptive immune response generated following infection is not well defined. Using a mouse model, we saw high IgG and IgA antibody titers in the serum and stool to TcdA following C. difficile infection. Further, to identify toxin specific CD4 +T cells, a peptide library was generated from the amino acid sequence of TcdA and subsequently used to test for peptide reactive T cells. CD4 +T cells from infected mice produced IL-17a following restimulation with TcdA peptides, with the number of peptide reactive CD4 +T cells correlating with TcdA specific antibody titers. Furthermore, cellular responses were confined to the gastrointestinal tract, with expansion of germinal center B cells, T follicular helper cells, and TcdA specific CD4 +T cells in the lamina propria and mesenteric lymph nodes, but not the spleen. Further characterization of the TcdA response led to identification of a major peptide of interest that will aid in future investigation of the adaptive immune response following C. difficile infection. Supported by grants from NIH (R01 AI158830-01, R21 AI164385)
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Kimura, Tadashi, Seigo Ono, and Tai Kubo. "Molecular Cloning and Sequence Analysis of the cDNAs Encoding Toxin-Like Peptides from the Venom Glands of Tarantula Grammostola rosea." International Journal of Peptides 2012 (February 29, 2012): 1–10. http://dx.doi.org/10.1155/2012/731293.
Full textAbstract:
Tarantula venom glands produce a large variety of bioactive peptides. Here we present the identification of venom components obtained by sequencing clones isolated from a cDNA library prepared from the venom glands of the Chilean common tarantula, Grammostola rosea. The cDNA sequences of about 1500 clones out of 4000 clones were analyzed after selection using several criteria. Forty-eight novel toxin-like peptides (GTx1 to GTx7, and GTx-TCTP and GTx-CRISP) were predicted from the nucleotide sequences. Among these peptides, twenty-four toxins are ICK motif peptides, eleven peptides are MIT1-like peptides, and seven are ESTX-like peptides. Peptides similar to JZTX-64, aptotoxin, CRISP, or TCTP are also obtained. GTx3 series possess a cysteine framework that is conserved among vertebrate MIT1, Bv8, prokineticins, and invertebrate astakines. GTx-CRISP is the first CRISP-like protein identified from the arthropod venom. Real-time PCR revealed that the transcripts for TCTP-like peptide are expressed in both the pereopodal muscle and the venom gland. Furthermore, a unique peptide GTx7-1, whose signal and prepro sequences are essentially identical to those of HaTx1, was obtained.
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Vlasenko, Anna E., Vasiliy G. Kuznetsov, and Timur Yu Magarlamov. "Investigation of Peptide Toxin Diversity in Ribbon Worms (Nemertea) Using a Transcriptomic Approach." Toxins 14, no. 8 (August 8, 2022): 542. http://dx.doi.org/10.3390/toxins14080542.
Full textAbstract:
Nemertea is a phylum of nonsegmented worms (supraphylum: Spiralia), also known as ribbon worms. The members of this phylum contain various toxins, including peptide toxins. Here, we provide a transcriptomic analysis of peptide toxins in 14 nemertean species, including Cephalothrix cf. simula, which was sequenced in the current study. The summarized data show that the number of toxin transcripts in the studied nemerteans varied from 12 to 82. The most represented groups of toxins were enzymes and ion channel inhibitors, which, in total, reached a proportion of 72% in some species, and the least represented were pore-forming toxins and neurotoxins, the total proportion of which did not exceed 18%. The study revealed that nemerteans possess a much greater variety of toxins than previously thought and showed that these animals are a promising object for the investigation of venom diversity and evolution, and in the search for new peptide toxins.
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Ramesh, N., F. Spertini, P. Scholl, and R. Geha. "A toxic shock syndrome toxin-1 peptide that shows homology to mycobacterial heat shock protein 18 is presented as conventional antigen to T cells by multiple HLA-DR alleles." Journal of Immunology 148, no. 4 (February 15, 1992): 1025–30. http://dx.doi.org/10.4049/jimmunol.148.4.1025.
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Abstract We observe that PBMC from most adults (16 of 18 subjects tested) show a small but significant in vitro proliferative response to a 30-amino acid-long peptide (peptide 2, amino acids 34-63) derived from toxic shock syndrome toxin. By contrast, PBMC from newborn blood and thymocytes do not proliferate to this peptide, and furthermore, peptide 2 did not displace the binding of radiolabeled TSST-1 to MHC class II positive cells, nor did it induce IL-1 beta mRNA in monocytes, indicating that this peptide does not behave as a superantigen. Proliferation of PBMC to peptide 2 could be blocked by anti-HLA-DR, but not by anti-HLA-DP or DQ mAb, suggesting that HLA-DR molecules are the restriction elements for the recognition of this peptide by T cells. This premise was further confirmed by demonstrating that mouse L cells transfected with human HLA-DR, but not HLA-DP or DQ molecules, supported the proliferation of purified T cells to peptide 2. Studies with subjects of known HLA-DR types showed that all types tested are capable of responding to this peptide, PBMC from adults exposed to mycobacterial Ag showed significantly better proliferative response to peptide 2 than unexposed adults. Studies with truncations of this peptide suggest that a "core" region of eight amino acids that is conserved between low m.w. heat shock proteins and peptide 2 may be critical to T cell recognition of this peptide. The universal presentation of peptide 2 by HLA-DR molecules may contribute to the widespread natural immunity observed against toxic shock syndrome toxin.
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Shin, Min Kyoung, In-Wook Hwang, Yunkyung Kim, Seung Tae Kim, Wonhee Jang, Seungki Lee, Woo Young Bang, Chang-Hwan Bae, and Jung-Suk Sung. "Antibacterial and Anti-Inflammatory Effects of Novel Peptide Toxin from the Spider Pardosa astrigera." Antibiotics 9, no. 7 (July 19, 2020): 422. http://dx.doi.org/10.3390/antibiotics9070422.
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The prevalence of antibiotic-resistant bacteria has become an immediate threat to public health. Antimicrobial peptides are attracting attention as a new source of antibiotics due to their ability to prevent drug-resistances with fewer side effects. Spider venom is composed of various bioactive substances with multiple functionalities such as antimicrobial and anti-inflammatory effects. Here, RNA sequencing was conducted on the venom gland of the spider Pardosa astrigera, and a potential toxin peptide with antibacterial properties was selected via homology and in silico analysis. A novel toxin, Lycotoxin-Pa4a, inhibited both gram-negative and gram-positive bacteria by disrupting the outer and bacterial cytoplasmic membrane. Moreover, the peptide downregulated the expression of pro-inflammatory mediators while upregulating the level of anti-inflammatory cytokine by inactivating mitogen-activated protein kinase signaling in a lipopolysaccharide-stimulated murine macrophage cell line. In this research, we identified a novel peptide toxin, Lycotoxin-pa4a, with antibacterial and anti-inflammatory properties, suggesting its potential for the development of a new antibiotics, as well as offering insights into the utilization of biological resources.
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Weaver, Keith E., Shirisha G. Reddy, Cassandra L. Brinkman, Smita Patel, Kenneth W. Bayles, and Jennifer L. Endres. "Identification and characterization of a family of toxin–antitoxin systems related to the Enterococcus faecalis plasmid pAD1 par addiction module." Microbiology 155, no. 9 (September 1, 2009): 2930–40. http://dx.doi.org/10.1099/mic.0.030932-0.
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The par locus of the Enterococcus faecalis plasmid pAD1 is an RNA-regulated addiction module encoding the peptide toxin Fst. Homology searches revealed that Fst belongs to a family of at least nine related peptides encoded on the chromosomes and plasmids of six different Gram-positive bacterial species. Comparison of an alignment of these peptides with the results of a saturation mutagenesis analysis indicated regions of the peptides important for biological function. Examination of the genetic context of the fst genes revealed that all of these peptides are encoded within par-like loci with conserved features similar to pAD1 par. All four Ent. faecalis family members were demonstrated to produce the expected toxin-encoding and regulatory RNA products. The locus from the Ent. faecalis plasmid pAMS1 was demonstrated to function as an addiction module and Fst was shown to be toxic to Staphylococcus aureus, suggesting that a plasmid-encoded module in that species is performing the same function. Thus, the pAD1-encoded par locus appears to be the prototype of a family of related loci found in several Gram-positive species.
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Zhao, Ruiming, Hui Dai, Netanel Mendelman, Jordan H. Chill, and Steve A. N. Goldstein. "Tethered peptide neurotoxins display two blocking mechanisms in the K+ channel pore as do their untethered analogs." Science Advances 6, no. 10 (March 2020): eaaz3439. http://dx.doi.org/10.1126/sciadv.aaz3439.
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We show here that membrane-tethered toxins facilitate the biophysical study of the roles of toxin residues in K+ channel blockade to reveal two blocking mechanisms in the K+ channel pore. The structure of the sea anemone type I (SAK1) toxin HmK is determined by NMR. T-HmK residues are scanned by point mutation to map the toxin surface, and seven residues are identified to be critical to occlusion of the KcsA channel pore. T-HmK–Lys22 is shown to interact with K+ ions traversing the KcsA pore from the cytoplasm conferring voltage dependence on the toxin off rate, a classic mechanism that we observe as well with HmK in solution and for Kv1.3 channels. In contrast, two related SAK1 toxins, Hui1 and ShK, block KcsA and Kv1.3, respectively, via an arginine rather than the canonical lysine, when tethered and as free peptides.
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Kumkoon, Tipaporn, Chalongrat Noree, and Panadda Boonserm. "Engineering BinB Pore-Forming Toxin for Selective Killing of Breast Cancer Cells." Toxins 15, no. 4 (April 18, 2023): 297. http://dx.doi.org/10.3390/toxins15040297.
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Breast cancer is one of the most common cancers in women worldwide. Conventional cancer chemotherapy always has adverse side effects on the patient’s healthy tissues. Consequently, combining pore-forming toxins with cell-targeting peptides (CTPs) is a promising anticancer strategy for selectively destroying cancer cells. Here, we aim to improve the target specificity of the BinB toxin produced from Lysinibacillus sphaericus (Ls) by fusing a luteinizing hormone-releasing hormone (LHRH) peptide to its pore-forming domain (BinBC) to target MCF-7 breast cancer cells as opposed to human fibroblast cells (Hs68). The results showed that LHRH-BinBC inhibited MCF-7 cell proliferation in a dose-dependent manner while leaving Hs68 cells unaffected. BinBC, at any concentration tested, did not affect the proliferation of MCF-7 or Hs68 cells. In addition, the LHRH-BinBC toxin caused the efflux of the cytoplasmic enzyme lactate dehydrogenase (LDH), demonstrating the efficacy of the LHRH peptide in directing the BinBC toxin to damage the plasma membranes of MCF-7 cancer cells. LHRH-BinBC also caused MCF-7 cell apoptosis by activating caspase-8. In addition, LHRH-BinBC was predominantly observed on the cell surface of MCF-7 and Hs68 cells, without colocalization with mitochondria. Overall, our findings suggest that LHRH-BinBC could be investigated further as a potential cancer therapeutic agent.
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Bu, Ying, Fei Wang, Wenhui Zhu, and Xuepeng Li. "Combining bioinformatic prediction and assay experiment to identify novel xanthine oxidase inhibitory peptides from Pacific bluefin tuna (Thunnus Orientalis)." E3S Web of Conferences 185 (2020): 04062. http://dx.doi.org/10.1051/e3sconf/202018504062.
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In this work, we aim to combine bioinformatic prediction with a special experiment to search xanthine oxidase (XOD) inhibitory peptides from myosin of Pacific bluefin tuna (Thunnus Orientalis). The program Peptide Cutter, Peptide Ranker, Peptide Property calculator, Toxin Pred, and Discovery Studio (DS) help us screen the probable sequence. The result indicated that peptide ICRK has the highest inhibition effect and the value of IC50 was 14.18 mg/mL. The IC50 of the other two peptides (FDAK and MMER) were 16.8mg/mL and 15.3 mg/mL respectively. Molecular simulation demonstrated that ICRK interacted with amino acid residues GLU802, PHE914, ALA1079, GLU1261, LYS771, LEU648, THR1010, VAL1011 and SER 876. The possible inhibition mechanism of peptides and enzyme was stated by DS. Peptide ICRK blocked the entrance to the hydrophobic channel and stopped xanthine going into the active site of XOD. MMER and FDAK have the similar mechanism with ICRK. Therefore, ICRK, FDAK and MMER can be considered as nature XOD inhibitory peptides and further utilized.
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Neilan, Brett A., Elke Dittmann, Leo Rouhiainen, R. Amanda Bass, Verena Schaub, Kaarina Sivonen, and Thomas Börner. "Nonribosomal Peptide Synthesis and Toxigenicity of Cyanobacteria." Journal of Bacteriology 181, no. 13 (July 1, 1999): 4089–97. http://dx.doi.org/10.1128/jb.181.13.4089-4097.1999.
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ABSTRACT Nonribosomal peptide synthesis is achieved in prokaryotes and lower eukaryotes by the thiotemplate function of large, modular enzyme complexes known collectively as peptide synthetases. These and other multifunctional enzyme complexes, such as polyketide synthases, are of interest due to their use in unnatural-product or combinatorial biosynthesis (R. McDaniel, S. Ebert-Khosla, D. A. Hopwood, and C. Khosla, Science 262:1546–1557, 1993; T. Stachelhaus, A. Schneider, and M. A. Marahiel, Science 269:69–72, 1995). Most nonribosomal peptides from microorganisms are classified as secondary metabolites; that is, they rarely have a role in primary metabolism, growth, or reproduction but have evolved to somehow benefit the producing organisms. Cyanobacteria produce a myriad array of secondary metabolites, including alkaloids, polyketides, and nonribosomal peptides, some of which are potent toxins. This paper addresses the molecular genetic basis of nonribosomal peptide synthesis in diverse species of cyanobacteria. Amplification of peptide synthetase genes was achieved by use of degenerate primers directed to conserved functional motifs of these modular enzyme complexes. Specific detection of the gene cluster encoding the biosynthetic pathway of the cyanobacterial toxin microcystin was shown for both cultured and uncultured samples. Blot hybridizations, DNA amplifications, sequencing, and evolutionary analysis revealed a broad distribution of peptide synthetase gene orthologues in cyanobacteria. The results demonstrate a molecular approach to assessing preexpression microbial functional diversity in uncultured cyanobacteria. The nonribosomal peptide biosynthetic pathways detected may lead to the discovery and engineering of novel antibiotics, immunosuppressants, or antiviral agents.