Iterative peptide backbone N-methylation in borosin RiPP biosynthesis Michael Freeman University of Minnesota, USA Amide backbone α- N -methylations bestow favorable characteristics to natural products such as increased structural rigidity, proteolytic resistance, and enhanced pharmacodynamic properties. Although these modified peptides have been known for well over 40 years, we only recently uncovered a biosynthetic process that post-translationally incorporates α- N -methylations into ribosomally translated peptides. The first borosin RiPP biosynthetic pathway was discovered to produce the nematicide omphalotin A in the basidiomycete Omphalotus olearius in 2017. 1 Since this discovery, a large number of putative pathways have been identified in a wide range of fungi and bacteria. In this talk, I will outline our most recent results in the discovery and characterization of borosin RiPP pathways. Structural and functional characterization of borosin RiPP enzymes and peptides has unveiled surprisingly varied methyltransferase and RiPP precursor architectures. 2-4 All in all, our work highlights the increasing structural complexity found in ribosomally synthesized peptide natural products and their dynamic biosynthetic machineries. References 1. Van der Velden, NS, Kälin, N, Helf, MJ, Piel, J, Freeman, MF , Künzler, M( 2017 ) Autocatalytic backbone N -methylation in a family of ribosomal peptide natural products, Nat. Chem. Biol. 13(8): 833-835. DOI: 10.1038/nchembio.2393. 2. Quijano, MR, Zach, C, Miller, FS, Lee, AR, Imani, AS, Künzler, M, Freeman, MF ( 2019 ) Distinct autocatalytic α- N -methylating precursors expand the borosin RiPP family of peptide natural products. J. Am. Chem. Soc., 141(24): 9637-9644 . DOI: 10.1021/jacs.9b03690. 3. Miller, FS, Crone, KK, Jensen, MR, Shaw, S, Harcombe, WR, Elias, MH, Freeman, MF ( 2021 ) Conformational rearrangements enable iterative backbone N -methylation in RiPP biosynthesis. Nat. Comm. 12(1): 5355. DOI: 10.1038/ s41467-021-25575-7. 4. Imani, AS, Lee, AR, Vishwanathan, N, de Waal, F, Freeman, MF ( 2021 ) Diverse protein architectures and α- N -methylation patterns define split borosin RiPP biosynthetic gene clusters. bioRxiv DOI: 10.1101/2021.12.24.474128.
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