Genome mining unveils a class of ribosomal peptides with two amino termini

Hengqian Ren, Shravan R. Dommaraju, Chunshuai Huang, Haiyang Cui, Yuwei Pan, Marko Nesic, Lingyang Zhu, David Sarlah, Douglas A. Mitchell () and Huimin Zhao ()
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Hengqian Ren: University of Illinois at Urbana-Champaign
Shravan R. Dommaraju: University of Illinois at Urbana-Champaign
Chunshuai Huang: University of Illinois at Urbana-Champaign
Haiyang Cui: University of Illinois at Urbana-Champaign
Yuwei Pan: University of Illinois at Urbana-Champaign
Marko Nesic: University of Illinois at Urbana-Champaign
Lingyang Zhu: University of Illinois at Urbana-Champaign
David Sarlah: University of Illinois at Urbana-Champaign
Douglas A. Mitchell: University of Illinois at Urbana-Champaign
Huimin Zhao: University of Illinois at Urbana-Champaign

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: Abstract The era of inexpensive genome sequencing and improved bioinformatics tools has reenergized the study of natural products, including the ribosomally synthesized and post-translationally modified peptides (RiPPs). In recent years, RiPP discovery has challenged preconceptions about the scope of post-translational modification chemistry, but genome mining of new RiPP classes remains an unsolved challenge. Here, we report a RiPP class defined by an unusual (S)-N2,N2-dimethyl-1,2-propanediamine (Dmp)-modified C-terminus, which we term the daptides. Nearly 500 daptide biosynthetic gene clusters (BGCs) were identified by analyzing the RiPP Recognition Element (RRE), a common substrate-binding domain found in half of prokaryotic RiPP classes. A representative daptide BGC from Microbacterium paraoxydans DSM 15019 was selected for experimental characterization. Derived from a C-terminal threonine residue, the class-defining Dmp is installed over three steps by an oxidative decarboxylase, aminotransferase, and methyltransferase. Daptides uniquely harbor two positively charged termini, and thus we suspect this modification could aid in membrane targeting, as corroborated by hemolysis assays. Our studies further show that the oxidative decarboxylation step requires a functionally unannotated accessory protein. Fused to the C-terminus of the accessory protein is an RRE domain, which delivers the unmodified substrate peptide to the oxidative decarboxylase. This discovery of a class-defining post-translational modification in RiPPs may serve as a prototype for unveiling additional RiPP classes through genome mining.

Date: 2023
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DOI: 10.1038/s41467-023-37287-1

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