Distinct Autocatalytic α- N-Methylating Precursors Expand the Borosin RiPP Family of Peptide Natural Products

Marissa R. Quijano, Christina Zach, Fredarla S. Miller, Aileen R. Lee, Aman S. Imani, Markus Künzler, Michael F. Freeman

Research output: Contribution to journalArticlepeer-review

15 Scopus citations


Backbone N-methylations impart several favorable characteristics to peptides including increased proteolytic stability and membrane permeability. Nonetheless, amide bond N-methylations incorporated as post-translational modifications are scarce in nature and were first demonstrated in 2017 for a single set of fungal metabolites. Here we expand on our previous discovery of iterative, autocatalytic α-N-methylating precursor proteins in the borosin family of ribosomally encoded peptide natural products. We identify over 50 putative pathways in a variety of ascomycete and basidiomycete fungi and functionally validate nearly a dozen new self-α-N-methylating catalysts. Significant differences in precursor size, architecture, and core peptide properties subdivide this new peptide family into three discrete structural types. Lastly, using targeted genomics, we link the biosynthetic origins of the potent antineoplastic gymnopeptides to the borosin natural product family. This work highlights the metabolic potential of fungi for ribosomally synthesized peptide natural products.

Original languageEnglish (US)
Pages (from-to)9637-9644
Number of pages8
JournalJournal of the American Chemical Society
Issue number24
StatePublished - Jun 19 2019

Bibliographical note

Funding Information:
We would like to thank Dr. Robert Blanchette for strains of B. adusta, C. unicolor, and P. gigantea and for helpful discussions. We thank Daniel L. Lindner for a strain of P. chrysoloma. We also thank Dr. Hannelore Kaspar for discussions concerning mass spectrometry. This work was financially supported by the University of Minnesota, the Microbial Engineering program, and the BioTechnology Institute Biocatalysis Initiative for M.F.F. and the Swiss National Science Foundation (grant no. 31003A_173097) for M.K.

Publisher Copyright:
© 2019 American Chemical Society.


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