Fischerazoles A-C, cyanobacterial polychlorinated lipids featuring fatty acyl chain rearrangement

Fatty acyl moieties are a very common feature of cyanobacterial secondary metabolites. Using a recently developed method to discover fatty acyl-containing natural products, we detected and isolated three new lipopeptides – fisch-erazoles A-C (1-3) – from the cyanobacterium Fischerella sp. PCC 9431. These metabolites present extensive halo-genation in their fatty acyl moiety as well as an unusual pendant allyl alcohol. We analyzed the genome sequence of the producing cyanobacterium and identified a putative biosynthetic gene cluster associated with the fischera-zoles, based on bioinformatic analysis. Using stable-isotope precursor feeding experiments, we identified the key substrates for the biosynthesis of 1-3. Surprisingly, we found that hexadecanoic acid was fully incorporated into fischerazoles, despite the fact that these compounds have a linear 15-carbon chain. Additional feeding experiments with stable-isotope labeled fatty acids established a one-carbon contraction of the palmitic acid-derived alkyl chain, and that the remaining carbon branches out as part of the pendant allyl alcohol group. This rearrangement, which leads to the functionalization of a mid-chain aliphatic carbon, might be of interest for biocatalysis. Our findings reinforce the utility of metabolomics-based methods to uncover natural product scaffolds with a high degree of novelty.