Fischerazoles A-C, cyanobacterial polychlorinated lipids featuring fatty acyl chain rearrangement Kathleen Abt 1,2 , Sandra A. C. Figueiredo 1 , Teresa P. Martins 1,2 , Iñaki Lacomba 1 , Abel M. Forero 3 , Carlos Jiménez 3 , Jaime Rodríguez 3 , Pedro N. Leão 1 1 CIIMAR - Interdisciplinary Centre of Marine and Environmental Research, Portugal 2 University of Porto, Portugal, 3 Universidade da Coruña, Spain Cyanobacteria are a growing source of bioactive natural products with potential for biotechnological and pharmacological applications. Many cyanobacterial secondary metabolites contain fatty acid moieties. Our group has recently developed a method to exploit this feature for detection of novel compounds by supplementation of stable isotope-labeled fatty acids and comparative metabolomics. Using this method on the cyanobacterium Fischerella sp. PCC 9431, we discovered a new group of lipopeptides that we named fischerazoles A-C. These compounds had particularly interesting structural features such as extensive chlorination of the fatty acyl chain, a rare gem- dichlorovinylidene moiety, a pendant allyl alcohol and an unusual terminal methylated carboxamide. By mining the genome of PCC 9431 for halogenases, we detected a putative biosynthetic gene cluster (BGC) of polyketide synthase (PKS)/ non-ribosomal peptide synthetase (NRPS) nature. Bioinformatics and supplementation experiments with stable isotope-labeled precursors indicated a connection between the fischerazoles and the candidate BGC ( fsh ). Surprisingly, although the fischerazoles only have a linear 15-carbon chain, hexadecanoic acid (C16) was fully incorporated into these compounds. By additional supplementation experiments, we found that during biosynthesis the fatty acid substrate must be rearranged to branch out into the pendant allyl alcohol moiety. The enzymes involved in this functionalization of a mid-chain aliphatic carbon could be of interest for biocatalysis. These findings highlight the advantage of metabolomics-based methods in the discovery of highly novel chemical structures.
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© The Author(s), 2022
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