The vast majority of microorganisms on the planet have not been grown under laboratory conditions due to unknown metabolic and environmental constraints. This uncultivated majority has enormous potential as a reservoir of unique enzymology and biosynthetic pathways. The following review offers a glimpse into this unexplored enzymatic stockpile through recent progress made on the biosynthesis of the potent polytheonamide cytotoxins. These structurally highly complex pore-forming peptides, isolated from the marine sponge Theonella swinhoei, are synthesized by the ribosome and then modified through numerous unusual transformations including iterative epimerase and N-methyltransferase activities. The bacterial source of these metabolites was identified as the taxonomically remote, uncultivated sponge symbiont 'Entotheonella factor' with a biosynthetic prowess that rivals those of industrially exploited microorganisms.
Bibliographical noteFunding Information:
We would like to thank Eike Peters for providing the ‘Entotheonella’ image depicted in Figure 3 . We would also like to thank Maximillian J. Helf and Micheal C. Wilson for helpful suggestions and editing of the manuscript. Work in the authors’ lab was supported by the Deutsche Forschungsgemeinschaft ( PI 430/9-1 ), the EU (BlueGenics, BluePharmTrain, and SYNPEPTIDE), the SNF ( IZLSZ3_149025 and 31003A_146992/1 ), and a Japan Society for the Promotion of Science Visiting Professorship to J.P., as well as by an ETH Zurich Postdoctoral Fellowship to A.L.V. and a Human Frontier Science Program Long-Term Fellowship to M.F.F.