Venom Peptide Repertoire of the European Myrmicine Ant <i>Manica rubida</i>: Identification of Insecticidal Toxins

Touchard, Axel; Aili, Samira R.; Téné, Nathan; Barassé, Valentine; Klopp, Christophe; Déjean, Alain; Kini, R. Manjunatha; Mrinalini, _; Coquet, Laurent; Jouenne, Thierry; Lefranc, Benjamin; Leprince, Jérôme; Escoubas, Pierre; Nicholson, Graham M.; Treilhou, Michel; Bonnafé, Elsa

doi:10.1021/acs.jproteome.0c00048

Cited by 35 publications

(44 citation statements)

References 45 publications

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“…P17, downsized and alanine-substituted analogues were synthesized by Fmoc solid-phase methodology on a Liberty microwave-assisted automated peptide synthesizer (CEM, Saclay, France) using the standard manufacturer's procedures at 0.1 mmol scale as previously described. 37 All Fmoc-amino acids (0.5 mmol, 5 eq.) were coupled on preloaded Fmoc-Leu-, Fmoc-Ile-, Fmoc-Glu(OtBu)-, or Fmoc-Ala-Wang resin by in situ activation with HBTU (0.5 mmol, 5 eq.)…”

Section: Pharmacophore Region and Alanine Scanning Of Peptide P17mentioning

confidence: 99%

P17 induces chemotaxis and differentiation of monocytes via MRGPRX2-mediated mast cell–line activation

Duraisamy

Singh

Kumar

et al. 2022

Journal of Allergy and Clinical Immunology

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Background: P17, a peptide isolated from Tetramorium bicarinatum ant venom, is known to induce an alternative phenotype of human monocyte-derived macrophages via activation of an unknown G protein-coupled receptor (GPCR). Objective: We sought to investigate the mechanism of action and the immunomodulatory effects of P17 mediated through MRGPRX2 (Mas-related G protein-coupled receptor X2). Methods: To identify the GPCR for P17, we screened 314 GPCRs. Upon identification of MRGPRX2, a battery of in silico, in vitro, ex vivo, and in vivo assays along with the receptor mutation studies were performed. In particular, to investigate the immunomodulatory actions, we used b-hexosaminidase release assay, cytokine releases, quantification of mRNA expression, cell migration and differentiation assays, immunohistochemical labeling, hematoxylin and eosin, and immunofluorescence staining. Results: P17 activated MRGPRX2 in a dose-dependent manner in b-arrestin recruitment assay. In LAD2 cells, P17 induced calcium and b-hexosaminidase release. Quercetin-and short hairpin RNA-mediated knockdown of MRGPRX2 reduced P17evoked b-hexosaminidase release. In silico and in vitro mutagenesis studies showed that residue Lys 8 of P17 formed a cation-p interaction with the Phe 172 of MRGPRX2 and [Ala 8 ] P17 lost its activity partially. P17 activated LAD2 cells to recruit THP-1 and human monocytes in Transwell migration assay, whereas MRGPRX2-impaired LAD2 cells cannot. In addition, P17-treated LAD2 cells stimulated differentiation of THP-1 and

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Section: Pharmacophore Region and Alanine Scanning Of Peptide P17mentioning

confidence: 99%

P17 induces chemotaxis and differentiation of monocytes via MRGPRX2-mediated mast cell–line activation

Duraisamy

Singh

Kumar

et al. 2022

Journal of Allergy and Clinical Immunology

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“…All peptides and derivatives were synthesized by the solid phase methodology on Rink amide MBHA resin using a Liberty microwave-assisted automated peptide synthesizer (CEM, Saclay, France) and the standard manufacturer’s procedures at 0.1 mmol scale as previously described [ 54 ]. All Fmoc-amino acids and building blocks (0.5 mmol, 5 equiv) were coupled by in situ activation with HBTU (0.5 mmol, 5 equiv) and DIEA (1 mmol, 10 equiv).…”

Section: Methodsmentioning

confidence: 99%

Point-Substitution of Phenylalanine Residues of 26RFa Neuropeptide: A Structure-Activity Relationship Study

et al. 2021

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26RFa is a neuropeptide that activates the rhodopsin-like G protein-coupled receptor QRFPR/GPR103. This peptidergic system is involved in the regulation of a wide array of physiological processes including feeding behavior and glucose homeostasis. Herein, the pharmacological profile of a homogenous library of QRFPR-targeting peptide derivatives was investigated in vitro on human QRFPR-transfected cells with the aim to provide possible insights into the structural determinants of the Phe residues to govern receptor activation. Our work advocates to include in next generations of 26RFa(20–26)-based QRFPR agonists effective substitutions for each Phe unit, i.e., replacement of the Phe22 residue by a constrained 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid moiety, and substitution of both Phe24 and Phe26 by their para-chloro counterpart. Taken as a whole, this study emphasizes that optimized modifications in the C-terminal part of 26RFa are mandatory to design selective and potent peptide agonists for human QRFPR.

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“…Peptides C2 28–63 -A 61 d3 and C2 28–63 -A 61 d4 were synthesized by Fmoc solid phase methodology on a Liberty microwave assisted automated peptide synthesizer (CEM, Saclay, France) using the standard manufacturer's procedures at 0.1 mmol scale as previously described ( 58 ). Briefly, all Fmoc-amino acids (0.5 mmol, 5 eq.)…”

Section: Methodsmentioning

confidence: 99%

Biosynthesis of the sactipeptide Ruminococcin C by the human microbiome: Mechanistic insights into thioether bond formation by radical SAM enzymes

Balty

Guillot

Fradale

et al. 2020

Journal of Biological Chemistry

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Despite its major importance in human health, the metabolic potential of the human gut microbiota is still poorly understood. We have recently shown that biosynthesis of Ruminococcin C (RumC), a novel ribosomally synthesized and post-translationally modified peptide (RiPP) produced by the commensal bacterium Ruminococcus gnavus, requires two radical SAM enzymes (RumMC1 and RumMC2) catalyzing the formation of four Cα-thioether bridges. These bridges, which are essential for RumC’s antibiotic properties against human pathogens such as Clostridium perfringens, define two hairpin domains giving this sactipeptide (sulfur-to–α-carbon thioether-containing peptide) an unusual architecture among natural products. We report here the biochemical and spectroscopic characterizations of RumMC2. EPR spectroscopy and mutagenesis data support that RumMC2 is a member of the large family of SPASM-domain radical SAM enzymes characterized by the presence of three [4Fe-4S] clusters. We also demonstrate that this enzyme initiates its reaction by Cα H-atom abstraction and is able to catalyze the formation of non-natural thioether bonds in engineered peptide substrates. Unexpectedly, our data support the formation of a ketoimine rather than an α,β-dehydro-amino acid intermediate during Cα-thioether bridge LC-MS/MS fragmentation. Finally, we explored the roles of the leader peptide and of the RiPP precursor peptide recognition element (RRE), present in myriad RiPP-modifying enzymes. Collectively, our data support a more complex role for the RRE and the core peptide for the installation of post-translational modifications in RiPPs than previously anticipated and suggest a possible reaction intermediate for thioether bond formation.

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Venom Peptide Repertoire of the European Myrmicine Ant Manica rubida: Identification of Insecticidal Toxins

Cited by 35 publications

References 45 publications

P17 induces chemotaxis and differentiation of monocytes via MRGPRX2-mediated mast cell–line activation

P17 induces chemotaxis and differentiation of monocytes via MRGPRX2-mediated mast cell–line activation

Point-Substitution of Phenylalanine Residues of 26RFa Neuropeptide: A Structure-Activity Relationship Study

Biosynthesis of the sactipeptide Ruminococcin C by the human microbiome: Mechanistic insights into thioether bond formation by radical SAM enzymes

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