Bioinformatics-guided discovery of biaryl-linked lasso peptides

• Published in: Chemical science (Cambridge) 2023-11, Vol.14 (45), p.13176-13183
• Main Authors: Saad, Hamada, Majer, Thomas, Bhattarai, Keshab, Lampe, Sarah, Nguyen, Dinh T, Kramer, Markus, Straetener, Jan, Brötz-Oesterhelt, Heike, Mitchell, Douglas A, Gross, Harald
• Format: Article
• Language: English
• Subjects: Bioinformatics; Cytochromes P450; Mass spectrometry; NMR; Nuclear magnetic resonance; Peptides; Scientific imaging; Structural analysis
• ISSN: 2041-6520; 2041-6539
• DOI: 10.1039/d3sc02380j

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. Using mass spectrometry, stable isotope incorporation, and extensive 2D-NMR spectrometry, we report the structural characterization of two unique examples of (C-N) biaryl-linked lasso peptides. Nocapeptin A, from Nocardia terpenica , is tailored with a Trp-Tyr crosslink, while longipepetin A, from Longimycelium tulufanense , features a Trp-Trp linkage. Besides the unusual bicyclic frame, a Met of longipepetin A undergoes S -methylation to yield a trivalent sulfonium, a heretofore unprecedented RiPP modification. A bioinformatic survey revealed additional lasso peptide BGCs containing P450 enzymes which await future characterization. Lastly, nocapeptin A bioactivity was assessed against a panel of human and bacterial cell lines with modest growth-suppression activity detected towards Micrococcus luteus . Genome mining enabled the discovery of a series of unique lasso peptides. They contain a P450-mediated C-N-based biarylic crosslink at the lasso ring and can in addition bear a unique sulfonium residue.