A biaryl-linked tripeptide from Planomonospora reveals a widespread class of minimal RiPP gene clusters

Mitja M. Zdouc*, M.M. Alanjary, Guadelupe S. Zarazúa, Sonia I. Maffioli, M. Crüsemann, M.H. Medema, Stefano Donadio, Margherita Sosio*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

31 Citations (Scopus)


Microbial natural products impress by their bioactivity, structural diversity, and ingenious biosynthesis. While screening the less exploited actinobacterial genus Planomonospora, two cyclopeptides were discovered, featuring an unusual Tyr-His biaryl bridging across a tripeptide scaffold, with the sequences N-acetyl-Tyr-Tyr-His and N-acetyl-Tyr-Phe-His. Planomonospora genomes pointed toward a ribosomal synthesis of the cyclopeptide from a pentapeptide precursor encoded by 18-bp bytA, to our knowledge the smallest coding gene ever reported. Closely linked to bytA is bytO, encoding a cytochrome P450 monooxygenase likely responsible for biaryl installment. In Streptomyces, the bytAO segment was sufficient to direct production of the crosslinked N-acetylated Tyr-Tyr-His tripeptide. Bioinformatic analysis of related cytochrome P450 monooxygenases indicated that they constitute a widespread family of enzymes, and the corresponding genes are closely linked to 5-amino acid coding sequences in approximately 200 (actino)bacterial genomes, all with potential for biaryl linkage between amino acids 1 and 3. We propose the named biarylitides this family of RiPPs.
Original languageEnglish
Pages (from-to)733-739.e4
JournalCell Chemical Biology
Issue number5
Early online date14 Dec 2020
Publication statusPublished - 2021


  • actinomycetes
  • biaryls
  • heterologous expression
  • minimal BGC
  • phylogenomics
  • RiPPs


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