Peptide backbone N-methylation, as seen in cyclosporin A, has been considered to be exclusive to nonribosomal peptides. We have identified the first post-translationally modified peptide or protein harboring internal α-N-methylations through discovery of the genetic locus for the omphalotins, cyclic N-methylated peptides produced by the fungus Omphalotus olearius. We show that iterative autocatalytic activity of an N-methyltransferase fused to its peptide substrate is the signature of a new family of ribosomally encoded metabolites.
Bibliographical noteFunding Information:
We thank M. Aebi for helpful discussions and continuous support, J. Thorner for helpful suggestions regarding the manuscript, the functional genomics center Zürich for ESI–TOF–MS measurements, A. Brachmann for help with HPLC–MS/MS HCD measurements, A. Imani for performing cell-free experiments and C.W. Lin for help with HPLC–MS/MS ETD measurements. We are grateful to L. Nagy and F. Martin for sharing unpublished genome and transcriptome data of Dendrothele bispora CBS 962.96 and Marasmius fiardii PR-910, respectively, produced and made publicly available by the US Department of Energy Joint Genome Institute (DOE JGI). This work was supported by ETH Zürich (M.K. and J.P.), the University of Minnesota (M.F.F.), the Swiss National Science Foundation (31003A_146992) (J.P.), and the EU 7th framework program (SYNPEPTIDE) (J.P.).