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Analysis of the Reaction Coordinate of α-L-Fucosidases: A Combined Structural and Quantum Mechanical Approach
DOI:
10.1021/ja908908q
PMID:
20092273
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

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
Added On:
29/09/2011 22:45
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