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  • Title: Analysis of the reaction coordinate of alpha-L-fucosidases: a combined structural and quantum mechanical approach.
    Author: Lammerts van Bueren A, Ardèvol A, Fayers-Kerr J, Luo B, Zhang Y, Sollogoub M, Blériot Y, Rovira C, Davies GJ.
    Journal: J Am Chem Soc; 2010 Feb 17; 132(6):1804-6. PubMed ID: 20092273.
    Abstract:
    The enzymatic hydrolysis of alpha-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 alpha-L-fucosidase unveiling a Michaelis (ES) complex in a (1)C(4) (chair) conformation and a covalent glycosyl-enzyme intermediate in (3)S(1) (skew-boat). First principles metadynamics simulations on isolated alpha-L-fucose strongly support a (1)C(4)<-->(3)H(4)<-->(3)S(1) conformational itinerary for the glycosylation step of the reaction mechanism and indicate a strong "preactivation" of the (1)C(4) 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.
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