Enzyme-primed native chemical ligation produces autoinducing cyclopeptides in clostridia.

Molloy EM, Dell M, Haensch VG, Dunbar KL, Feldmann R, Oberheide A, Seyfarth L, Kumpfmüller J, Horch T, Arndt HD, Hertweck C (2021) Enzyme-primed native chemical ligation produces autoinducing cyclopeptides in clostridia. Angew Chem Int Ed 60(19), 10670-10679.

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 have remained elusive. Here, we report the genome-guided discovery of a cyclic AIP (cAIP) that controls endospore formation in Ruminiclostridium cellulolyticum . Through a combination of chemical synthesis and chemical complementation assays with mutant strain, we reveal that a homodetic cyclopeptide is the genuine chemical mediator. Kinetic analyses indicate that the mature cAIP is produced via a cryptic thiolactone intermediate that undergoes a rapid S → N 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 cAIPs.

Leibniz-HKI-Authors

Christian Hertweck
Jana Krabbe
Kyle Dunbar
Evelyn Molloy
Maria Dell
Veit Hänsch
Romy Feldmann
Therese Horch

Identifier

doi: 10.1002/anie.202016378

PMID: 33625794