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Analysis of the Reaction Coordinate of α-L-Fucosidases: A Combined Structural and Quantum Mechanical Approach

DOI: 10.1021/ja908908q DOI Help
PMID: 20092273 PMID Help

Authors: Alicia Lammerts Van Bueren (Department of Biochemistry and Microbiology, University of Victoria) , Jennifer Fayers-kerr (ICREA) , Bo Luo (UPMC-Univ Paris 06.) , Yongmin Zhang (UPMC-Univ Paris 06.) , Matthieu Sollogoub (UPMC-Univ Paris 06.) , Yves Blériot (UPMC-Univ Paris 06.) , Carme Rovira (Parc Científic de Barcelona) , Gideon Davies (ICREA)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of The American Chemical Society , VOL 132 (6) , PAGES 1804 - 1806

State: Published (Approved)
Published: February 2010

Open Access Open Access

Abstract: The enzymatic hydrolysis of α-l-fucosides is of importance in cancer, bacterial infections, and fucosidosis, a neurodegenerative lysosomal storage disorder. Here we show a series of snapshots along the reaction coordinate of a glycoside hydrolase family GH29 α-l-fucosidase unveiling a Michaelis (ES) complex in a 1C4 (chair) conformation and a covalent glycosyl-enzyme intermediate in 3S1 (skew-boat). First principles metadynamics simulations on isolated α-l-fucose strongly support a 1C4↔3H4↔3S1 conformational itinerary for the glycosylation step of the reaction mechanism and indicate a strong “preactivation” of the 1C4 complex to nucleophilic attack as reflected by free energy, C1−O1/O5−C1 bond length elongation/reduction, C1−O1 bond orientation, and positive charge development around the anomeric carbon. Analysis of an imino sugar inhibitor is consistent with tight binding of a chair-conformed charged species.

Journal Keywords: Fucose; Humans; Models; Molecular; Protein; Quantum; Sequence; Amino; Thermodynamics; alpha-L-Fucosidase

Subject Areas: Biology and Bio-materials

Instruments: I02-Macromolecular Crystallography