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

Author

Listed:
  • 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
    Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology)

  • Qian Che

    (Ocean University of China
    Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology)

  • Tianjiao Zhu

    (Ocean University of China
    Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology)

  • Dehai Li

    (Ocean University of China
    Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology)

  • Qianqun Gu

    (Ocean University of China
    Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology)

  • Wenli Li

    (Ocean University of China
    Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology)

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.

Suggested Citation

  • Tingting Yao & Jing Liu & Zengzhi Liu & Tong Li & Huayue Li & Qian Che & Tianjiao Zhu & Dehai Li & Qianqun Gu & Wenli Li, 2018. "Genome mining of cyclodipeptide synthases unravels unusual tRNA-dependent diketopiperazine-terpene biosynthetic machinery," Nature Communications, Nature, vol. 9(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-06411-x
    DOI: 10.1038/s41467-018-06411-x
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    Cited by:

    1. Michael P. Andreas & Tobias W. Giessen, 2024. "Cyclodipeptide oxidase is an enzyme filament," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    2. Garrett Deletti & Sajan D. Green & Caleb Weber & Kristen N. Patterson & Swapnil S. Joshi & Tushar M. Khopade & Mathew Coban & James Veek-Wilson & Thomas R. Caulfield & Rajesh Viswanathan & Amy L. Lane, 2023. "Unveiling an indole alkaloid diketopiperazine biosynthetic pathway that features a unique stereoisomerase and multifunctional methyltransferase," Nature Communications, Nature, vol. 14(1), pages 1-13, December.

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