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Radical SAM-dependent ether crosslink in daropeptide biosynthesis

Author

Listed:
  • Sijia Guo

    (Shanghai Jiao Tong University)

  • Shu Wang

    (Fudan University)

  • Suze Ma

    (Fudan University)

  • Zixin Deng

    (Shanghai Jiao Tong University)

  • Wei Ding

    (Shanghai Jiao Tong University)

  • Qi Zhang

    (Fudan University)

Abstract

Darobactin is a ribosomally synthesized and post-translationally modified peptide (RiPP), which possesses potent activity against various Gram-negative bacteria. Darobactin features a highly unique bicyclic scaffold, consisting of an ether crosslink between two Trp residues and a C–C crosslink between a Lys and a Trp. Here we report in vivo and in vitro activity of darobactin synthase DarE. We show DarE is a radical S-adenosylmethionine (rSAM) enzyme and is solely responsible for forming the bicyclic scaffold of darobactin. DarE mainly produced the ether-crosslinked product in vitro, and when the assay was performed in H218O, apparent 18O incorporation was observed into the ether-crosslinked product. These observations suggested an rSAM-dependent process in darobactin biosynthesis, involving a highly unusual oxygen insertion step from a water molecule and subsequent O–H and C–H activations. Genome mining analysis demonstrates the diversity of darobactin-like biosynthetic gene clusters, a subclade of which likely encode monocyclic products with only an ether linkage. We propose the name daropeptide for this growing family of ether-containing RiPPs produced by DarE enzymes.

Suggested Citation

  • Sijia Guo & Shu Wang & Suze Ma & Zixin Deng & Wei Ding & Qi Zhang, 2022. "Radical SAM-dependent ether crosslink in daropeptide biosynthesis," Nature Communications, Nature, vol. 13(1), pages 1-9, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30084-2
    DOI: 10.1038/s41467-022-30084-2
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    1. Yu Imai & Kirsten J. Meyer & Akira Iinishi & Quentin Favre-Godal & Robert Green & Sylvie Manuse & Mariaelena Caboni & Miho Mori & Samantha Niles & Meghan Ghiglieri & Chandrashekhar Honrao & Xiaoyu Ma , 2019. "A new antibiotic selectively kills Gram-negative pathogens," Nature, Nature, vol. 576(7787), pages 459-464, December.
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    Cited by:

    1. Yuqing Li & Yeying Ma & Yinzheng Xia & Tao Zhang & Shuaishuai Sun & Jiangtao Gao & Hongwei Yao & Huan Wang, 2023. "Discovery and biosynthesis of tricyclic copper-binding ribosomal peptides containing histidine-to-butyrine crosslinks," Nature Communications, Nature, vol. 14(1), pages 1-12, December.

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