Genome mining of cyclodipeptide synthases unravels unusual tRNA-dependent diketopiperazine-terpene biosynthetic machinery

Tingting Yao, Jing Liu, Zengzhi Liu, Tong Li, Huayue Li, Qian Che, Tianjiao Zhu, Dehai Li, Qianqun Gu and Wenli Li ()
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Tingting Yao: Ocean University of China
Jing Liu: Ocean University of China
Zengzhi Liu: Ocean University of China
Tong Li: Ocean University of China
Huayue Li: Ocean University of China
Qian Che: Ocean University of China
Tianjiao Zhu: Ocean University of China
Dehai Li: Ocean University of China
Qianqun Gu: Ocean University of China
Wenli Li: Ocean University of China

Nature Communications, 2018, vol. 9, issue 1, 1-12

Abstract: Abstract Cyclodipeptide synthases (CDPSs) can catalyze the formation of two successive peptide bonds by hijacking aminoacyl-tRNAs from the ribosomal machinery resulting in diketopiperazines (DKPs). Here, three CDPS-containing loci (dmt1–3) are discovered by genome mining and comparative genome analysis of Streptomyces strains. Among them, CDPS DmtB1, encoded by the gene of dmt1 locus, can synthesize cyclo(L-Trp-L-Xaa) (with Xaa being Val, Pro, Leu, Ile, or Ala). Systematic mutagenesis experiments demonstrate the importance of the residues constituting substrate-binding pocket P1 for the incorporation of the second aa-tRNA in DmtB1. Characterization of dmt1–3 unravels that CDPS-dependent machinery is involved in CDPS-synthesized DKP formation followed by tailoring steps of prenylation and cyclization to afford terpenylated DKP compounds drimentines. A phytoene-synthase-like family prenyltransferase (DmtC1) and a membrane terpene cyclase (DmtA1) are required for drimentines biosynthesis. These results set the foundation for further increasing the natural diversity of complex DKP derivatives.

Date: 2018
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DOI: 10.1038/s41467-018-06411-x

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