Radical SAM-dependent ether crosslink in daropeptide biosynthesis

Sijia Guo, Shu Wang, Suze Ma, Zixin Deng, Wei Ding () and Qi Zhang ()
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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

Nature Communications, 2022, vol. 13, issue 1, 1-9

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-30084-2

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