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Enzyme‐Primed Native Chemical Ligation Produces Autoinducing Cyclopeptides in Clostridia
Author(s) -
Molloy Evelyn M.,
Dell Maria,
Hänsch Veit G.,
Dunbar Kyle L.,
Feldmann Romy,
Oberheide Ansgar,
Seyfarth Lydia,
Kumpfmüller Jana,
Horch Therese,
Arndt HansDieter,
Hertweck Christian
Publication year - 2021
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.202016378
Subject(s) - chemistry , biochemistry , native chemical ligation , enzyme , clostridia , chemical synthesis , complementation , intramolecular force , bioorthogonal chemistry , stereochemistry , quorum sensing , biology , mutant , computational biology , combinatorial chemistry , genetics , bacteria , gene , in vitro , virulence , click chemistry
Abstract Clostridia coordinate many important processes such as toxin production, infection, and survival by density‐dependent communication (quorum sensing) using autoinducing peptides (AIPs). Although clostridial AIPs have been proposed to be (thio)lactone‐containing peptides, their true structures remain elusive. Here, we report the genome‐guided discovery of an AIP that controls endospore formation in Ruminiclostridium cellulolyticum . Through a combination of chemical synthesis and chemical complementation assays with a mutant strain, we reveal that the genuine chemical mediator is a homodetic cyclopeptide (cAIP). Kinetic analyses indicate that the mature cAIP is produced via a cryptic thiolactone intermediate that undergoes a rapid S → N acyl shift, in a manner similar to intramolecular native chemical ligation (NCL). Finally, by implementing a chemical probe in a targeted screen, we show that this novel enzyme‐primed, intramolecular NCL is a widespread feature of clostridial AIP biosynthesis.