Producing engineered lipopeptides via the ribosomal route Nina Bösch , Annina R. Meyer, Johannes A. Eckert, Florian Hubrich, Anna L. Vagstad and Jörn Piel ETH Zürich, Switzerland The engineering of many natural product classes remains challenging considering their biosynthetic route. But one potential candidate for biosynthetic engineering are the ribosomally synthetized and post-translationally modified peptides (RiPPs). Since their underlying peptide sequence is defined by a genetically encoded precursor peptide one could easily alter the final peptide sequence in combination with the post-translational modifications introduced by closely encoded maturase enzymes 1 . We recently characterized a novel class of post-translational modifications in RiPPs comprising the introduction of medium-chain fatty acids (MCFAs) onto sidechain amino groups of lysines and ornithines by a GCN5-related acetyl-transferase. Three representative systems were characterized where each acyl-transferase introduced a distinct fatty acid onto their corresponding precursor peptide 2 . Further we showed initial success in introducing altered core peptide sequences (the final RiPP product) to our systems, where corresponding fatty acid modifications were introduced independently of the underlying peptide sequence. Similarly, we could show a partial peptide position independence of the acyl-transferases for the residues to be modified. This is a promising start to allow us to produce designer lipopeptides in a directed manner and therefore produce potentially bioactive compounds invaluable for pharmaceutical applications. References
1. Montalbán-López, et al., Prod. Rep. 2021 , 38 (1), 130-239 2. Hubrich and Bösch, et al., Natl. Acad. Sci. 2022, 119 (3)
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