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Toblerols: Cyclopropanol‐Containing Polyketide Modulators of Antibiosis in Methylobacteria
Author(s) -
Ueoka Reiko,
BortfeldMiller Miriam,
Morinaka Brandon I.,
Vorholt Julia A.,
Piel Jörn
Publication year - 2018
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201709056
Subject(s) - polyketide , methylotroph , complementation , stereochemistry , chemistry , natural product , gene cluster , polyketide synthase , moiety , biosynthesis , antibiosis , bacteria , biology , biochemistry , gene , genetics , phenotype
Trans ‐AT polyketide synthases (PKSs) are a family of biosynthetically versatile modular type I PKSs that generate bioactive polyketides of impressive structural diversity. In this study, we detected, in the genome of several bacteria a cryptic, architecturally unusual trans ‐AT PKS gene cluster which eluded automated PKS prediction. Genomic mining of one of these strains, the model methylotroph Methylobacterium extorquens AM1, revealed unique epoxide‐ and cyclopropanol‐containing polyketides named toblerols. Relative and absolute stereochemistry were determined by NMR experiments, chemical derivatization, and the comparison of CD data between the derivatized natural product and a synthesized model compound. Biosynthetic data suggest that the cyclopropanol moiety is generated by carbon–carbon shortening of a more extended precursor. Surprisingly, a knock‐out strain impaired in polyketide production showed strong inhibitory activity against other methylobacteria in contrast to the wild‐type producer. The activity was inhibited by complementation with toblerols, thus suggesting that these compounds modulate an as‐yet unknown methylobacterial antibiotic.