Bioinformatics-Guided Discovery of Biaryl-Tailored Lasso Peptides

Saad, H.; Majer, T.; Bhattarai, K.; Lampe, S.; Nguyen, D. T.; Kramer, M.; Straetener, J.; Broetz-Oesterhelt, H.; Mitchell, D. A.; Gross, H.

doi:10.1101/2023.03.06.531328

bioRxiv · 10.1101/2023.03.06.531328

Bioinformatics-Guided Discovery of Biaryl-Tailored Lasso Peptides

Saad, H.·Majer, T.·Bhattarai, K.·Lampe, S.·Nguyen, D. T.·Kramer, M.·Straetener, J.·Broetz-Oesterhelt, H.·Mitchell, D. A.·Gross, H.

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Abstract

Lasso peptides are a class of ribosomally synthesized and post-translationally modified peptides (RiPPs) that feature an isopeptide bond and a distinct lariat fold. A growing number of secondary modifications have been described that further decorate lasso peptide scaffolds. Using genome mining, we have discovered a pair of lasso peptide biosynthetic gene clusters (BGCs) that include cytochrome P450 genes. Here, we report the structural characterization of two unique examples of (C-N) biaryl-containing lasso peptides. Nocapeptin A, from Nocardia terpenica, is tailored with Trp-Tyr crosslink while longipepetin A, from Longimycelium tulufanense, features Trp-Trp linkage. Besides the unusual bicyclic frame, longipepetin A receives an S-methylation by a new Met methyltransferase resulting in unprecedented sulfonium-bearing RiPP. Our bioinformatic survey revealed P450(s) and further maturating enzyme(s)-containing lasso BGCs awaiting future characterization.

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Saad, H., Majer, T., Bhattarai, K., Lampe, S., Nguyen, D. T., Kramer, M., Straetener, J., Broetz-Oesterhelt, H., Mitchell, D. A., Gross, H.. 2023-03-06. Bioinformatics-Guided Discovery of Biaryl-Tailored Lasso Peptides. https://doi.org/10.1101/2023.03.06.531328

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