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Nguyen, Lisa ; Schlotte, Luca ; Hoffmann, Julian ; Betz, Dominik ; Schröder, Marius ; Hahn, Frank:
Covalent warhead assembly in fostriecin biosynthesis involves malonylation-lactonisation by a bifunctional thioesterase and enzymatic demalonylation.
In: Nature Communications.
Bd. 17
(2026)
.
- 2365.
ISSN 2041-1723
DOI: https://doi.org/10.1038/s41467-026-70144-5
Angaben zu Projekten
| Projekttitel: |
Offizieller Projekttitel Projekt-ID Open Access Publizieren Ohne Angabe |
|---|---|
| Projektfinanzierung: |
Boehringer Ingelheim-Stiftung VolkswagenStiftung |
Abstract
α,β-Unsaturated δ-lactones (AUDLs) are key pharmacophores of various polyketides exhibiting potent biological activity. Fostriecin has attracted interest as an anticancer agent, but its structural characteristics have limited its development and motivated investigations into biosynthesis-based production strategies. Here, we elucidate the enzymatic steps responsible for AUDL formation in fostriecin biosynthesis by in vitro reconstitution using complex synthetic substrate surrogates. We demonstrate that the terminal polyketide synthase (PKS) module FosMod8 produces a 3-O-malonyllactone by the unusual bifunctional thioesterase FosTE, which catalyses O-malonylation and subsequent lactonisation. Structural modelling and site-directed mutagenesis reveal two arginine residues in the active site of FosTE that mediate malonyl-CoA binding and transesterification, thereby enabling the domain to mimic PKS acyltransferase chemistry. Additionally, we show that AUDL formation is carried out by the demalonylating enzyme FosM, whose activity strongly depends on prior fostriecin backbone phosphorylation by the broad-specific kinase FosH. This arrangement optimises the biosynthesis of phosphorylated AUDL metabolites by minimising shunt intermediate formation and losses from spontaneous side reactions of sensitive intermediates. This unique enzymatic logic represents a blueprint for other AUDLs and understanding it paves the way for new synthetic strategies to AUDL polyketides using chemoenzymatic synthesis or engineered biosynthesis.