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Microviridin 1777: A Toxic Chymotrypsin Inhibitor Discovered by a Metabologenomic Approach

  • Simon Sieber
    Simon Sieber
    Department of Chemistry, University of Zurich, Winterthurerstrasse 190, Zurich, CH 8057, Switzerland
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  • , 
  • Simone M. Grendelmeier
    Simone M. Grendelmeier
    Department of Chemistry, University of Zurich, Winterthurerstrasse 190, Zurich, CH 8057, Switzerland
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  • , 
  • Lonnie A. Harris
    Lonnie A. Harris
    Department of Chemistry, University of Illinois at Urbana−Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, United States
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  • , 
  • Douglas A. Mitchell
    Douglas A. Mitchell
    Department of Chemistry, University of Illinois at Urbana−Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, United States
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    Orcidhttp://orcid.org/0000-0002-9564-0953
  • , and 
  • Karl Gademann*
    Karl Gademann
    Department of Chemistry, University of Zurich, Winterthurerstrasse 190, Zurich, CH 8057, Switzerland
    *E-mail: [email protected]
    More by Karl Gademann
    Orcidhttp://orcid.org/0000-0003-3053-0689
Cite this: J. Nat. Prod. 2020, 83, 2, 438–446
Publication Date (Web):January 28, 2020
https://doi.org/10.1021/acs.jnatprod.9b00986
Copyright © 2020 American Chemical Society and American Society of Pharmacognosy
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    Abstract

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    The toxicity of the cyanobacterium Microcystis aeruginosa EAWAG 127a was evaluated against the sensitive grazer Thamnocephalus platyurus, and the extract possessed strong activity. To investigate the compounds responsible for cytotoxicity, a series of peptides from this cyanobacterium were studied using a combined genomic and molecular networking approach. The results led to the isolation, structure elucidation, and biological evaluation of microviridin 1777, which represents the most potent chymotrypsin inhibitor characterized from this family of peptides to date. Furthermore, the biosynthetic gene clusters of microviridin, anabaenopeptin, aeruginosin, and piricyclamide were located in the producing organism, and six additional natural products were identified by tandem mass spectrometry analyses. These results highlight the potential of modern techniques for the identification of natural products, demonstrate the ecological role of protease inhibitors produced by cyanobacteria, and raise ramifications concerning the presence of novel, yet uncharacterized, toxin families in cyanobacteria beyond microcystin.

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jnatprod.9b00986.

    • HPLC chromatogram, MS, UV, and NMR spectra, molecular networking analysis, serine protease and toxicity assays, and lists of microviridin natural products, detected RiPPs, and peptides (PDF)

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