Epidithiodiketopiperazine Biosynthesis: A Four-Enzyme Cascade Converts Glutathione Conjugates into Transannular Disulfide Bridges

Authors

  • Dr. Daniel H. Scharf,

    1. Depts. of Molecular and Applied Microbiology, Biomolecular Chemistry, and Bio Pilot Plant, Leibniz Institute for Natural Product Research and Infection Biology, HKI, Beutenbergstrasse 11a, 07745 Jena (Germany)
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    • These authors contributed equally to this work.

  • Pranatchareeya Chankhamjon,

    1. Depts. of Molecular and Applied Microbiology, Biomolecular Chemistry, and Bio Pilot Plant, Leibniz Institute for Natural Product Research and Infection Biology, HKI, Beutenbergstrasse 11a, 07745 Jena (Germany)
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    • These authors contributed equally to this work.

  • Dr. Kirstin Scherlach,

    1. Depts. of Molecular and Applied Microbiology, Biomolecular Chemistry, and Bio Pilot Plant, Leibniz Institute for Natural Product Research and Infection Biology, HKI, Beutenbergstrasse 11a, 07745 Jena (Germany)
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  • Dr. Thorsten Heinekamp,

    1. Depts. of Molecular and Applied Microbiology, Biomolecular Chemistry, and Bio Pilot Plant, Leibniz Institute for Natural Product Research and Infection Biology, HKI, Beutenbergstrasse 11a, 07745 Jena (Germany)
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  • Karsten Willing,

    1. Depts. of Molecular and Applied Microbiology, Biomolecular Chemistry, and Bio Pilot Plant, Leibniz Institute for Natural Product Research and Infection Biology, HKI, Beutenbergstrasse 11a, 07745 Jena (Germany)
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  • Prof. Dr. Axel A. Brakhage,

    1. Depts. of Molecular and Applied Microbiology, Biomolecular Chemistry, and Bio Pilot Plant, Leibniz Institute for Natural Product Research and Infection Biology, HKI, Beutenbergstrasse 11a, 07745 Jena (Germany)
    2. Friedrich Schiller University, Jena (Germany)
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  • Prof. Dr. Christian Hertweck

    Corresponding author
    1. Depts. of Molecular and Applied Microbiology, Biomolecular Chemistry, and Bio Pilot Plant, Leibniz Institute for Natural Product Research and Infection Biology, HKI, Beutenbergstrasse 11a, 07745 Jena (Germany)
    2. Friedrich Schiller University, Jena (Germany)
    • Depts. of Molecular and Applied Microbiology, Biomolecular Chemistry, and Bio Pilot Plant, Leibniz Institute for Natural Product Research and Infection Biology, HKI, Beutenbergstrasse 11a, 07745 Jena (Germany)

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  • We thank A. Perner for MS measurements, M. Poetsch for MALDI measurements, S. Fricke and C. Schult for technical assistance, P. Berthel for performing fermentations, M. Steinacker for downstream processing, P. Hortschansky for support in protein production, and A. Thywißen for providing the fluorescence microscope picture for the table of contents entry. This work was supported by the “Pakt für Forschung und Innovation” of the Free State of Thuringia and the BMBF, and the International Leibniz Research School for Biomolecular and Microbial Interactions (ILRS), as part of the excellence graduate school Jena School for Microbial Communication (JSMC).

Abstract

original image

Enzyme quartet: Isolation of the first sulfur-bearing intermediate of the gliotoxin pathway in Aspergillus fumigatus and successful in vitro conversion of the bisglutathione adduct into an intact epidithiodiketopiperazine by a four-enzyme cascade (including glutamyltransferase GliK and dipeptidase GliJ) revealed an outstanding adaptation of a primary metabolic pathway into natural product biosynthesis that is widespread in fungi.

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