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Core-dependent post-translational modifications guide the biosynthesis of a new class of hypermodified peptides

Author

Listed:
  • Zeng-Fei Pei

    (University of Illinois at Urbana-Champaign)

  • Lingyang Zhu

    (University of Illinois at Urbana-Champaign)

  • Satish K. Nair

    (University of Illinois at Urbana-Champaign
    University of Illinois at Urbana-Champaign
    University of Illinois at Urbana-Champaign)

Abstract

The ribosomally synthesized and post-translationally modified peptide (RiPPs) class of natural products has undergone significant expansion due to the rapid growth in genome sequencing data. Using a bioinformatics approach, we identify the dehydrazoles, a novel class of hypermodified RiPPs that contain both side chain dehydration of Ser residues, and backbone heterocyclization at Ser, Thr, and Cys residues to the corresponding azol(in)es. Structure elucidation of the hypermodified peptide carnazolamide, a representative class member, shows that 18 post-translational modifications are installed by just five enzymes. Complete biosynthetic reconstitution demonstrates that dehydration is carried out by an unusual DUF4135 dehydration domain fused to a zinc-independent cyclase domain (CcaM). We demonstrate that CcaM only modifies Ser residues that precede an azole in the core peptide. As heterocyclization removes the carbonyl following the Ser residue, CcaM likely catalyzes dehydration without generating an enolate intermediate. Additionally, CcaM does not require the leader peptide, and this core-dependence effectively sets the order for the biosynthetic reactions. Biophysical studies demonstrate direct binding of azoles to CcaM consistent with this azole moiety-dependent dehydration. Bioinformatic analysis reveals more than 50 related biosynthetic gene clusters that contain additional catalysts that may produce structurally diverse scaffolds.

Suggested Citation

  • Zeng-Fei Pei & Lingyang Zhu & Satish K. Nair, 2023. "Core-dependent post-translational modifications guide the biosynthesis of a new class of hypermodified peptides," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-43604-5
    DOI: 10.1038/s41467-023-43604-5
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    References listed on IDEAS

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    1. Hengqian Ren & Shravan R. Dommaraju & Chunshuai Huang & Haiyang Cui & Yuwei Pan & Marko Nesic & Lingyang Zhu & David Sarlah & Douglas A. Mitchell & Huimin Zhao, 2023. "Genome mining unveils a class of ribosomal peptides with two amino termini," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    2. Taro Ozaki & Kona Yamashita & Yuki Goto & Morito Shimomura & Shohei Hayashi & Shumpei Asamizu & Yoshinori Sugai & Haruo Ikeda & Hiroaki Suga & Hiroyasu Onaka, 2017. "Dissection of goadsporin biosynthesis by in vitro reconstitution leading to designer analogues expressed in vivo," Nature Communications, Nature, vol. 8(1), pages 1-13, April.
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