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Carbon extension in peptidylnucleoside biosynthesis by radical SAM enzymes

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Abstract

Nikkomycins and polyoxins are antifungal peptidylnucleoside antibiotics active against human and plant pathogens. Here we report that during peptidylnucleoside biosynthesis in Streptomyces cacaoi and S. tendae, the C5′ extension of the nucleoside essential for downstream structural diversification is catalyzed by a conserved radical S-adenosyl-L-methionine (SAM) enzyme, PolH or NikJ. This is distinct from the nucleophilic mechanism reported for antibacterial nucleosides and represents a new mechanism of nucleoside natural product biosynthesis.

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Figure 1: C5′ extension in antifungal peptidylnucleoside biosynthesis.
Figure 2: Characterization of PolH C209 variants.

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Acknowledgements

We thank G.R. Dubay for assistance with the MS measurements. We thank A.A. Ribeiro at the Duke NMR center for the assistance in collecting NMR data. This work was supported by the Duke University Medical Center and National Institute of General Medical Sciences R01 GM115729 (to K.Y.). EPR spectrometer was supported by an Institutional Development Grant (ID 2014-IDG-1017) from the North Carolina Biotechnology Center.

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Authors and Affiliations

  1. Department of Biochemistry, Duke University Medical Center, Durham, North Carolina, USA

    Edward A Lilla & Kenichi Yokoyama

  2. Department of Chemistry, Duke University, Durham, North Carolina, USA

    Kenichi Yokoyama

Authors
  1. Edward A Lilla
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  2. Kenichi Yokoyama
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Contributions

K.Y. conceived the project. K.Y. and E.A.L. designed the experiments. E.A.L. performed the experiments. K.Y. and E.A.L. analyzed the data and wrote the manuscript.

Corresponding author

Correspondence to Kenichi Yokoyama.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Results, Supplementary Tables 1–11 and Supplementary Figures 1–31. (PDF 6129 kb)

Supplementary Note

Synthetic Procedures (PDF 311 kb)

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Lilla, E., Yokoyama, K. Carbon extension in peptidylnucleoside biosynthesis by radical SAM enzymes. Nat Chem Biol 12, 905–907 (2016). https://doi.org/10.1038/nchembio.2187

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