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A biaryl-linked tripeptide from Planomonospora leads to widespread class of minimal RiPP gene clusters

By Mitja M Zdouc, Mohammad M Alanjary, Guadalupe S. Zarazúa, Sonia I. Maffioli, Max Crüsemann, Marnix H Medema, Stefano Donadio, Margherita Sosio

Posted 21 Jul 2020
bioRxiv DOI: 10.1101/2020.07.21.214643

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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