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Biosynthesis of Translation Inhibitor Klebsazolicin Proceeds through Heterocyclization and N-Terminal Amidine Formation Catalyzed by a Single YcaO Enzyme

  • Dmitrii Y. Travin
    Dmitrii Y. Travin
    Department of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Moscow, 119992, Russia
    Center for Data-Intensive Biomedicine and Biotechnology, Skolkovo Institute of Science and Technology, Skolkovo, 143025, Russia
  • Mikhail Metelev
    Mikhail Metelev
    Center for Data-Intensive Biomedicine and Biotechnology, Skolkovo Institute of Science and Technology, Skolkovo, 143025, Russia
    Institute of Gene Biology of the Russian Academy of Sciences, Moscow, 119334, Russia
  • Marina Serebryakova
    Marina Serebryakova
    Center for Data-Intensive Biomedicine and Biotechnology, Skolkovo Institute of Science and Technology, Skolkovo, 143025, Russia
    Department of Chemistry and A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, 119992, Russia
  • Ekaterina S. Komarova
    Ekaterina S. Komarova
    Department of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Moscow, 119992, Russia
    Center for Data-Intensive Biomedicine and Biotechnology, Skolkovo Institute of Science and Technology, Skolkovo, 143025, Russia
  • Ilya A. Osterman
    Ilya A. Osterman
    Department of Chemistry and A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, 119992, Russia
    Center for Translational Biomedicine, Skolkovo Institute of Science and Technology, Skolkovo, 143025, Russia
  • Dmitry Ghilarov*
    Dmitry Ghilarov
    Center for Data-Intensive Biomedicine and Biotechnology, Skolkovo Institute of Science and Technology, Skolkovo, 143025, Russia
    Institute of Gene Biology of the Russian Academy of Sciences, Moscow, 119334, Russia
    *[email protected]
  • , and 
  • Konstantin Severinov*
    Konstantin Severinov
    Center for Data-Intensive Biomedicine and Biotechnology, Skolkovo Institute of Science and Technology, Skolkovo, 143025, Russia
    Institute of Gene Biology of the Russian Academy of Sciences, Moscow, 119334, Russia
    Waksman Institute for Microbiology, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854, United States
    *[email protected]
Cite this: J. Am. Chem. Soc. 2018, 140, 16, 5625–5633
Publication Date (Web):March 30, 2018
https://doi.org/10.1021/jacs.8b02277
Copyright © 2018 American Chemical Society

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    Abstract

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    Klebsazolicin (KLB) is a recently discovered Klebsiella pneumonia peptide antibiotic targeting the exit tunnel of bacterial ribosome. KLB contains an N-terminal amidine ring and four azole heterocycles installed into a ribosomally synthesized precursor by dedicated maturation machinery. Using an in vitro system for KLB production, we show that the YcaO-domain KlpD maturation enzyme is a bifunctional cyclodehydratase required for the formation of both the core heterocycles and the N-terminal amidine ring. We further demonstrate that the amidine ring is formed concomitantly with proteolytic cleavage of azole-containing pro-KLB by a cellular protease TldD/E. Members of the YcaO family are diverse enzymes known to activate peptide carbonyls during natural product biosynthesis leading to the formation of azoline, macroamidine, and thioamide moieties. The ability of KlpD to simultaneously perform two distinct types of modifications is unprecedented for known YcaO proteins. The versatility of KlpD opens up possibilities for rational introduction of modifications into various peptide backbones.

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    • Figures S1–S7, Tables S1 and S2, detailed description of all experimental procedures (PDF)

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