Isolation of Verrucosins A–E from a Marine Verrucosispora sp. Reveals a Unifying Biosynthetic Hypothesis for Linear and Macrocyclic Polyketides
Year: 2025
Type: article
Abstract: High Resolution Image Download MS PowerPoint Slide As part of our long-standing program evaluating the biosynthetic complexity and biomedical potential of natural products from marine microbes, our attention was drawn to culture extracts from a Verrucosispora sp. (strain TAA-831), which produced multiple compounds with unique UV absorbance signatures and HRMS data. Large-scale fermentation and targeted isolation afforded verrucosins A–E ( 1–5 ), a mixture of linear and macrocyclic polyketides whose structures were determined through a synergistic combination of experimental, computational, and genomic approaches. The conserved sequence of methyl malonate and malonate motifs across the verrucosins implied a shared biosynthetic origin despite structural divergence as linear and cyclic congeners. Targeted genome mining revealed a lone type I/type III hybrid polyketide synthase biosynthetic gene cluster, vrs, that is likely responsible for verrucosin production. This revelation demonstrates for the first time that linear 3,5-dihydroxybenzenic ( 1 and 2 ) and cyclic ansamycin ( 3–5 ) polyketides can be naturally produced by a single biosynthetic gene cluster. The identification of the vrs cluster and bioinformatic prediction of the stereoselectivity of the embedded reductive domains within the modular type I polyketide synthase reinforced the NMR and computational stereochemical assignments for the co-isolates, particularly the stereochemically complex linear verrucosins ( 1 and 2 ).
Source: Journal of Natural Products
Language: English
Subfield: Pharmacology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,500
Award: G6219564612
OpenAlex ID: W4411257320