Toblerols: Cyclopropanol-Containing Polyketide Modulators of Antibiosis in Methylobacteria.
Reiko UeokaMiriam Bortfeld-MillerBrandon I MorinakaJulia A VorholtJörn PielPublished in: Angewandte Chemie (International ed. in English) (2017)
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.
Keyphrases
- wild type
- magnetic resonance
- electronic health record
- genome wide
- copy number
- escherichia coli
- big data
- machine learning
- small molecule
- ms ms
- deep learning
- high throughput
- single cell
- dna methylation
- high performance liquid chromatography
- computed tomography
- artificial intelligence
- gas chromatography mass spectrometry
- solid state
- tandem mass spectrometry