Discovery and Biosynthesis of Cihunamides, Macrocyclic Antibacterial RiPPs with a Unique C−N Linkage Formed by CYP450 Catalysis

Joon Soo An, Hyunbin Lee, Hyungyu Kim, Seungyeon Woo, Hyunsung Nam, Jayho Lee, Ji Yun Lee, Sang Jip Nam, Sang Kook Lee, Ki Bong Oh, Seokhee Kim, Dong Chan Oh

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

Cihunamides A–D (1–4), novel antibacterial RiPPs, were isolated from volcanic-island-derived Streptomyces sp. The structures of 1–4 were elucidated by 1H, 13C, and 15N NMR, MS, and chemical derivatization; they contain a tetrapeptide core composed of WNIW, cyclized by a unique C−N linkage between two Trp units. Genome mining of the producer strain revealed two biosynthetic genes encoding a cytochrome P450 enzyme and a precursor peptide. Heterologous co-expression of the core genes demonstrated the biosynthesis of cihunamides through P450-mediated oxidative Trp-Trp cross-linking. Further bioinformatic analysis uncovered 252 homologous gene clusters, including that of tryptorubins, which possess a distinct Trp-Trp linkage. Cihunamides do not display the non-canonical atropisomerism shown in tryptorubins, which are the founding members of the “atropitide” family. Therefore, we propose to use a new RiPP family name, “bitryptides”, for cihunamides, tryptorubins, and their congeners, wherein the Trp-Trp linkages define the structural class rather than non-canonical atropisomerism.

Original languageEnglish
Article numbere202300998
JournalAngewandte Chemie - International Edition
Volume62
Issue number26
DOIs
StatePublished - 26 Jun 2023

Bibliographical note

Funding Information:
This research was supported by the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT (2021R1A4A2001251 and 2020R1A2C2003518 to D.‐C. Oh) and the Ministry of Education (2021R1A2C1008730 to S. Kim; 2022R1A6A3A01086883 to H. Lee).

Publisher Copyright:
© 2023 Wiley-VCH GmbH.

Keywords

  • Antibacterial Natural Products
  • Biosynthesis
  • Cytochrome P450 Enzymes
  • RIPPs
  • Structural Elucidation

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