A Wagner-Meerwein-like rearrangement shapes the structures of the fischerazoles, cyanobacterial polychlorinated lipopeptides

The discovery of structurally unusual natural products inspires both the search for novel enzymatic transfor-mations and for new synthetic strategies. Here, we employ stable isotope-labeled precursor feeding and metabolomics to reveal highly unusual cyanobacterial lipopeptides – fischerazoles A-C. These metabolites con-tain a polychlorinated fatty acyl-derived moiety with a vinyl branch and an N-methylated carboxamide-thiazole terminus. Most strikingly, stable-isotope-labeled precursor supplementation showed that during fischerazole biosynthesis, a linear, hexadecanoic acid-derived intermediate is processed to yield the ultimately branched alkyl moiety. The branched-out carbon becomes part of the vinyl group together with an S-adenosyl methionine (SAM)-derived carbon. A polyketide synthase/non-ribosomal peptide synthetase (PKS/NRPS) biosynthetic gene cluster (BGC) associated with the fischerazoles was identified. In vitro assays revealed that the SAM depend-ent methyltranfesrae FshF catalyzes the alkyl chain rearrangement and concomitant vinyl group formation of an ACP-tethered unsaturated fatty acid. FshF-like enzymes, which are related to the well-characterized cyclo-propane fatty acid synthases (CFASs) can thus be explored for alkyl chain functionalization.