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Aliphatic Ether Bond Formation Expands the Scope of Radical SAM Enzymes in Natural Product Biosynthesis

  • Kenzie A. Clark
    Kenzie A. Clark
    Department of Chemistry, Princeton University, Princeton, New Jersey 08544, United States
  • Leah B. Bushin
    Leah B. Bushin
    Department of Chemistry, Princeton University, Princeton, New Jersey 08544, United States
  • , and 
  • Mohammad R. Seyedsayamdost*
    Mohammad R. Seyedsayamdost
    Department of Chemistry, Princeton University, Princeton, New Jersey 08544, United States
    Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544, United States
    *[email protected]
Cite this: J. Am. Chem. Soc. 2019, 141, 27, 10610–10615
Publication Date (Web):June 18, 2019
https://doi.org/10.1021/jacs.9b05151
Copyright © 2019 American Chemical Society

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    Abstract

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    The biosynthetic pathways of microbial natural products provide a rich source of novel enzyme-catalyzed transformations. Using a new bioinformatic search strategy, we recently identified an abundance of gene clusters for ribosomally synthesized and post-translationally modified peptides (RiPPs) that contain at least one radical S-adenosylmethionine (RaS) metalloenzyme and are regulated by quorum sensing. In the present study, we characterize a RaS enzyme from one such RiPP gene cluster and find that it installs an aliphatic ether cross-link at an unactivated carbon center, linking the oxygen of a Thr side chain to the α-carbon of a Gln residue. This reaction marks the first ether cross-link installed by a RaS enzyme. Additionally, it leads to a new heterocyclization motif and underlines the utility of our bioinformatics approach in finding new families of RiPP modifications.

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    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/jacs.9b05151.

    • Detailed materials and methods, HPLC-Qtof-MS analysis of substrates and products of the reaction with TqqB, 1D/2D NMR spectra and spectral annotation for the substrate and product peptides, HR-MS and HR-MS/MS analysis for TqqA substrate variants (PDF)

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