Microorganisms communicate using the molecular language of natural products. Amazingly, the vast majority of microorganisms on Earth are as-of-yet uncultivated or too difficult to genetically manipulate and directly study. Thus, the discovery of new natural products or description of new biocatalytic transformations occurring within NP pathways from these niche microbial sources often require heterologous expression in tractable microbes. This work describes the unexpected biosynthetic origins of a ribosomally synthesized and post-translationally modified peptide (RiPP) produced by a basidiomycete fungus. We provide evidence, through heterologous expression, for iteratively incorporated alpha-N-methylations into a ribosomally encoded precursor protein. This never-before-seen post-translational modification was thought for over forty years to be only accessible through nonribosomal peptide synthesis. Along with a very unusual leader peptide composition, this pathway hallmarks the designation of a new RiPP natural product family we termed borosins. We go on to show this borosin RiPP family can be easily engineered to create new alpha-N-methylated peptides in vivo through genetic recoding, a first for this type of tailoring reaction. This research adds to the handful of RiPPs so far discovered or described in fungi and highlights the vast metabolic potential of uncharacterized microorganisms.

New fungal RiPP family changes the rules for modified peptide biosynthesis

255th National Meeting (2018)

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