Unraveling the molecular mechanism of polysaccharide lyases for efficient alginate degradation

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. Aachmann, Carme Rovira () and Casper Wilkens ()
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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
Folmer Fredslund: Technical University of Denmark
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
Finn L. Aachmann: NTNU Norwegian University of Science and Technology
Carme Rovira: Universitat de Barcelona
Casper Wilkens: Technical University of Denmark

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-56754-5

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