TY - JOUR
T1 - Bioinformatics-guided discovery of biaryl-linked lasso peptides
AU - Saad, Hamada
AU - Majer, Thomas
AU - Bhattarai, Keshab
AU - Lampe, Sarah
AU - Nguyen, Dinh T.
AU - Kramer, Markus
AU - Straetener, Jan
AU - Brötz-Oesterhelt, Heike
AU - Mitchell, Douglas A.
AU - Gross, Harald
PY - 2023/10/30
Y1 - 2023/10/30
N2 - 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.
AB - 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.
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U2 - 10.1039/D3SC02380J
DO - 10.1039/D3SC02380J
M3 - Article
SN - 2041-6520
VL - 14
SP - 13176
EP - 13183
JO - Chemical Science
JF - Chemical Science
IS - 45
ER -