Metagenome mining reveals polytheonamides as posttranslationally modified ribosomal peptides

Michael F. Freeman, Cristian Gurgui, Maximilian J. Helf, Brandon I. Morinaka, Agustinus R. Uria, Neil J. Oldham, Hans Georg Sahl, Shigeki Matsunaga, Jörn Piel

Research output: Contribution to journalArticlepeer-review

227 Scopus citations


It is held as a paradigm that ribosomally synthesized peptides and proteins contain only L-amino acids. We demonstrate a ribosomal origin of the marine sponge - derived polytheonamides, exceptionally potent, giant natural-product toxins. Isolation of the biosynthetic genes from the sponge metagenome revealed a bacterial gene architecture. Only six candidate enzymes were identified for 48 posttranslational modifications, including 18 epimerizations and 17 methylations of nonactivated carbon centers. Three enzymes were functionally validated, which showed that a radical S-adenosylmethionine enzyme is responsible for the unidirectional epimerization of multiple and different amino acids. Collectively, these complex alterations create toxins that function as unimolecular minimalistic ion channels with near-femtomolar activity. This study broadens the biosynthetic scope of ribosomal systems and creates new opportunities for peptide and protein bioengineering.

Original languageEnglish (US)
Pages (from-to)387-390
Number of pages4
Issue number6105
StatePublished - Oct 19 2012


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