A biaryl-linked tripeptide from Planomonospora leads to widespread class of minimal RiPP gene clusters
Mitja M Zdouc,
Mohammad M Alanjary,
Guadalupe S. Zarazúa,
Sonia I. Maffioli,
Marnix H Medema,
Posted 21 Jul 2020
bioRxiv DOI: 10.1101/2020.07.21.214643
Posted 21 Jul 2020
Microbial natural products impress by their bioactivity, structural diversity and ingenious biosynthesis. While screening the rare actinobacterial genus Planomonospora, cyclopeptides 1A and 1B were discovered, featuring an unusual Tyr-His biaryl-bridging across a tripeptide scaffold, with the sequences N-acetyl-Tyr-Tyr-His (1A) and N-acetyl-Tyr-Phe-His (1B). Genome analysis of the 1A producing strain pointed towards a ribosomal synthesis of 1A, from a pentapeptide precursor encoded by the tiny 18-nucleotide gene bycA, to our knowledge the smallest gene ever reported. Further, biaryl instalment is performed by the closely linked gene bycB, encoding a cytochrome P450 monooxygenase. Biosynthesis of 1A was confirmed by heterologous production in Streptomyces, yielding the mature product. Bioinformatic analysis of related cytochrome P450 monooxygenases indicated that they constitute a widespread family of pathways, associated to 5-aa coding sequences in approximately 200 (actino)bacterial genomes, all with potential for a biaryl linkage between amino acids 1 and 3. We propose the name biarylicins for this newly discovered family of RiPPs. ### Competing Interest Statement S.I.M., M.S. and S.D. are employees and/or shareholders of Naicons Srl. M.M.Z. is a former employee of Naicons. M.H.M. is a co-founder of Design Pharmaceuticals and a member of the scientific advisory board of Hexagon Bio. The other authors declare that no competing interests exist.
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