Thioesterase-mediated side chain transesterification generates potent Gq signaling inhibitor FR900359
| Autor: | Hermes, Cornelia, Richarz, René, Wirtz, Daniel A., Patt, Julian, Hanke, Wiebke, Kehraus, Stefan, Voß, Jan Hendrik, Küppers, Jim, Ohbayashi, Tsubasa, Namasivayam, Vigneshwaran, Alenfelder, Judith, Inoue, Asuka, Mergaert, Peter, Gütschow, Michael, Müller, Christa E., Kostenis, Evi, König, Gabriele M., Crüsemann, Max |
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| Přispěvatelé: | Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Intéractions Plantes-Bactéries (PBI), Département Microbiologie (Dpt Microbio), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS) |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Natural products
Molecular Structure Chromobacterium [SDV]Life Sciences [q-bio] Science Esterases Medicinal chemistry Biosynthesis Article Hemiptera Molecular Docking Simulation Gene Knockout Techniques HEK293 Cells Bacterial Proteins Depsipeptides Animals GTP-Binding Protein alpha Subunits Gq-G11 Humans Peptides Signal Transduction |
| Zdroj: | Nature Communications, Vol 12, Iss 1, Pp 1-12 (2021) Nature Communications Nature Communications, 2021, 12 (1), pp.144. ⟨10.1038/s41467-020-20418-3⟩ Nature Communications, Nature Publishing Group, 2021, 12 (1), pp.144. ⟨10.1038/s41467-020-20418-3⟩ |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/s41467-020-20418-3⟩ |
| Popis: | The potent and selective Gq protein inhibitor depsipeptide FR900359 (FR), originally discovered as the product of an uncultivable plant endosymbiont, is synthesized by a complex biosynthetic system comprising two nonribosomal peptide synthetase (NRPS) assembly lines. Here we characterize a cultivable bacterial FR producer, enabling detailed investigations into biosynthesis and attachment of the functionally important FR side chain. We reconstitute side chain assembly by the monomodular NRPS FrsA and the non-heme monooxygenase FrsH, and characterize intermolecular side chain transesterification to the final macrocyclic intermediate FR-Core, mediated by the FrsA thioesterase domain. We harness FrsA substrate promiscuity to generate FR analogs with altered side chains and demonstrate indispensability of the FR side chain for efficient Gq inhibition by comparative bioactivity, toxicity and docking studies. Finally, evolution of FR and side chain biosynthesis is discussed based on bioinformatics analyses. Side chain transesterification boosts potency and target affinity of selective Gq inhibitor natural products. FR900359 (FR) is a Gq protein inhibitor depsipeptide isolated from an uncultivable plant endosymbiont and synthesized by non-ribosomal peptide synthetases. Here, the authors discover a cultivable bacterial FR producer and show that FrsA thioesterase domain catalyses intermolecular transesterification of the FR side chain to the depsipeptide core during biosynthesis, improving Gq inhibition properties. |
| Databáze: | OpenAIRE |
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