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Unraveling the molecular mechanism of polysaccharide lyases for efficient alginate degradation

Author

Listed:
  • José Pablo Rivas-Fernández

    (Universitat de Barcelona)

  • Marlene Vuillemin

    (Technical University of Denmark)

  • Bo Pilgaard

    (Technical University of Denmark)

  • Leesa J. Klau

    (NTNU Norwegian University of Science and Technology
    SINTEF Industry)

  • Folmer Fredslund

    (Technical University of Denmark
    Novo Nordisk A/S)

  • Charlotte Lund-Hanssen

    (NTNU Norwegian University of Science and Technology)

  • Ditte H. Welner

    (Technical University of Denmark)

  • Anne S. Meyer

    (Technical University of Denmark)

  • J. Preben Morth

    (Technical University of Denmark)

  • Flora Meilleur

    (North Carolina State University
    Oak Ridge National Laboratory)

  • Finn L. Aachmann

    (NTNU Norwegian University of Science and Technology)

  • Carme Rovira

    (Universitat de Barcelona
    Passeig Lluís Companys)

  • Casper Wilkens

    (Technical University of Denmark
    Novo Nordisk Pharmatech A/S)

Abstract

Alginate lyases (ALs) catalyze the depolymerization of brown macroalgae alginates, widely used naturally occurring polysaccharides. Their molecular reaction mechanism remains elusive due to the lack of catalytically competent Michaelis-Menten-like complex structures. Here, we provide structural snapshots and dissect the mechanism of mannuronan-specific ALs from family 7 polysaccharide lyases (PL7), employing time-resolved NMR, X-ray, neutron crystallography, and QM/MM simulations. We reveal the protonation state of critical active site residues, enabling atomic-level analysis of the reaction coordinate. Our approach reveals an endolytic and asynchronous syn β-elimination reaction, with Tyr serving as both Brønsted base and acid, involving a carbanion-type transition state. This study not only reconciles previous structural and kinetic discrepancies, but also establishes a comprehensive PL reaction mechanism which is most likely applicable across all enzymes of the PL7 family as well as other PL families.

Suggested Citation

  • José Pablo Rivas-Fernández & Marlene Vuillemin & Bo Pilgaard & Leesa J. Klau & Folmer Fredslund & Charlotte Lund-Hanssen & Ditte H. Welner & Anne S. Meyer & J. Preben Morth & Flora Meilleur & Finn L. , 2025. "Unraveling the molecular mechanism of polysaccharide lyases for efficient alginate degradation," Nature Communications, Nature, vol. 16(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56754-5
    DOI: 10.1038/s41467-025-56754-5
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