Metagenome Mining Reveals Polytheonamides as Posttranslationally Modified Ribosomal Peptides

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 r...

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Bibliographic Details
Published in:	Science (American Association for the Advancement of Science) 2012-10, Vol.338 (6105), p.387-390
Main Authors:	Freeman, Michael F., Gurgui, Cristian, Helf, Maximilian J., Morinaka, Brandon I., Uria, Agustinus R., Oldham, Neil J., Sahl, Hans-Georg, Matsunaga, Shigeki, Piel, Jörn
Format:	Article
Language:	eng
Subjects:	Amino Acid Sequence Amino acids Animals Bacteria Biochemistry Biological and medical sciences Biosynthesis DNA Enzymes Fundamental and applied biological sciences. Psychology Ion Channels - biosynthesis Ion Channels - metabolism Marine Marine Toxins - biosynthesis Marine Toxins - metabolism Metagenome Metagenomics Methylation Molecular and cellular biology Molecular genetics Molecular Sequence Data Open reading frames Operator regions Pathways Peptides Polymerase chain reaction Protein Biosynthesis Protein Processing, Post-Translational Proteins - metabolism Ribosomes - metabolism S-Adenosylmethionine - metabolism Sponges Theonella - microbiology Toxins Translation. Translation factors. Protein processing
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Summary:	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 posttrarelational 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.
ISSN:	0036-8075 1095-9203