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Chemical zymogens for the protein cysteinome

Author

Listed:
  • Mireia Casanovas Montasell

    (Aarhus University)

  • Pere Monge

    (Aarhus University)

  • Sheiliza Carmali

    (Aarhus University
    Queen’s University Belfast)

  • Livia Mesquita Dias Loiola

    (Aarhus University)

  • Dante Guldbrandsen Andersen

    (Aarhus University
    Aarhus University)

  • Kaja Borup Løvschall

    (Aarhus University)

  • Ane Bretschneider Søgaard

    (Aarhus University
    Aarhus University)

  • Maria Merrild Kristensen

    (Aarhus University)

  • Jean Maurice Pütz

    (Aarhus University)

  • Alexander N. Zelikin

    (Aarhus University
    Aarhus University)

Abstract

We present three classes of chemical zymogens established around the protein cysteinome. In each case, the cysteine thiol group was converted into a mixed disulfide: with a small molecule, a non-degradable polymer, or with a fast-depolymerizing fuse polymer (ZLA). The latter was a polydisulfide based on naturally occurring molecule, lipoic acid. Zymogen designs were applied to cysteine proteases and a kinase. In each case, enzymatic activity was successfully masked in full and reactivated by small molecule reducing agents. However, only ZLA could be reactivated by protein activators, demonstrating that the macromolecular fuse escapes the steric bulk created by the protein globule, collects activation signal in solution, and relays it to the active site of the enzyme. This afforded first-in-class chemical zymogens that are activated via protein-protein interactions. We also document zymogen exchange reactions whereby the polydisulfide is transferred between the interacting proteins via the “chain transfer” bioconjugation mechanism.

Suggested Citation

  • Mireia Casanovas Montasell & Pere Monge & Sheiliza Carmali & Livia Mesquita Dias Loiola & Dante Guldbrandsen Andersen & Kaja Borup Løvschall & Ane Bretschneider Søgaard & Maria Merrild Kristensen & Je, 2022. "Chemical zymogens for the protein cysteinome," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32609-1
    DOI: 10.1038/s41467-022-32609-1
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    References listed on IDEAS

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    1. Shidong Song & Alexander F. Mason & Richard A. J. Post & Marco Corato & Rafael Mestre & N. Amy Yewdall & Shoupeng Cao & Remco W. Hofstad & Samuel Sanchez & Loai K. E. A. Abdelmohsen & Jan C. M. Hest, 2021. "Author Correction: Engineering transient dynamics of artificial cells by stochastic distribution of enzymes," Nature Communications, Nature, vol. 12(1), pages 1-1, December.
    2. Shidong Song & Alexander F. Mason & Richard A. J. Post & Marco De Corato & Rafael Mestre & N. Amy Yewdall & Shoupeng Cao & Remco W. Hofstad & Samuel Sanchez & Loai K. E. A. Abdelmohsen & Jan C. M. Hes, 2021. "Engineering transient dynamics of artificial cells by stochastic distribution of enzymes," Nature Communications, Nature, vol. 12(1), pages 1-9, December.
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    1. Ane Bretschneider Søgaard & Andreas Bøtker Pedersen & Kaja Borup Løvschall & Pere Monge & Josefine Hammer Jakobsen & Leila Džabbarova & Line Friis Nielsen & Sandra Stevanovic & Raoul Walther & Alexand, 2023. "Transmembrane signaling by a synthetic receptor in artificial cells," Nature Communications, Nature, vol. 14(1), pages 1-10, December.

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