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

Alicia Lammerts van Bueren; Albert Ardevol; Jennifer Fayers-Kerr; Bo Luo; Yongmin Zhang; Matthieu Sollogoub; Yves Bleriot; Carme Rovira; Gideon J. Davies

doi:10.1021/ja908908q

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

Alicia Lammerts van Bueren, Albert Ardevol, Jennifer Fayers-Kerr, Bo Luo, Yongmin Zhang, Matthieu Sollogoub, Yves Bleriot, Carme Rovira, Gideon J. Davies

Chemistry

Research output: Contribution to journal › Article › peer-review

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 C-1(4) (chair) conformation and a covalent glycosyl-enzyme intermediate in S-3(1) (skew-boat). First principles metadynamics simulations on isolated alpha-l-fucose strongly support a C-1(4)<-> H-3(4)<-> S-3(1) conformational itinerary for the glycosylation step of the reaction mechanism and indicate a strong "preactivation" of the C-1(4) complex to nucleophilic attack as reflected by free energy, C1-O1/05-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.

Original language	English
Pages (from-to)	1804-+
Number of pages	5
Journal	Journal of the American Chemical Society
Volume	132
Issue number	6
DOIs	https://doi.org/10.1021/ja908908q
Publication status	Published - 17 Feb 2010

Keywords

MOLECULAR-DYNAMICS SIMULATIONS
GLYCOSYL-ENZYME INTERMEDIATE
TRANSITION-STATE
SUBSTRATE DISTORTION
THERMOTOGA-MARITIMA
CATALYTIC MECHANISM
CANCER
INSIGHTS
HYDROLASES
IDENTIFICATION

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10.1021/ja908908q

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title = "Analysis of the Reaction Coordinate of alpha-L-Fucosidases: A Combined Structural and Quantum Mechanical Approach",

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 C-1(4) (chair) conformation and a covalent glycosyl-enzyme intermediate in S-3(1) (skew-boat). First principles metadynamics simulations on isolated alpha-l-fucose strongly support a C-1(4)<-> H-3(4)<-> S-3(1) conformational itinerary for the glycosylation step of the reaction mechanism and indicate a strong {"}preactivation{"} of the C-1(4) complex to nucleophilic attack as reflected by free energy, C1-O1/05-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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author = "{van Bueren}, {Alicia Lammerts} and Albert Ardevol and Jennifer Fayers-Kerr and Bo Luo and Yongmin Zhang and Matthieu Sollogoub and Yves Bleriot and Carme Rovira and Davies, {Gideon J.}",

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T1 - Analysis of the Reaction Coordinate of alpha-L-Fucosidases: A Combined Structural and Quantum Mechanical Approach

AU - van Bueren, Alicia Lammerts

AU - Ardevol, Albert

AU - Fayers-Kerr, Jennifer

AU - Luo, Bo

AU - Zhang, Yongmin

AU - Sollogoub, Matthieu

AU - Bleriot, Yves

AU - Rovira, Carme

AU - Davies, Gideon J.

PY - 2010/2/17

Y1 - 2010/2/17

N2 - 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 C-1(4) (chair) conformation and a covalent glycosyl-enzyme intermediate in S-3(1) (skew-boat). First principles metadynamics simulations on isolated alpha-l-fucose strongly support a C-1(4)<-> H-3(4)<-> S-3(1) conformational itinerary for the glycosylation step of the reaction mechanism and indicate a strong "preactivation" of the C-1(4) complex to nucleophilic attack as reflected by free energy, C1-O1/05-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.

AB - 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 C-1(4) (chair) conformation and a covalent glycosyl-enzyme intermediate in S-3(1) (skew-boat). First principles metadynamics simulations on isolated alpha-l-fucose strongly support a C-1(4)<-> H-3(4)<-> S-3(1) conformational itinerary for the glycosylation step of the reaction mechanism and indicate a strong "preactivation" of the C-1(4) complex to nucleophilic attack as reflected by free energy, C1-O1/05-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.

KW - MOLECULAR-DYNAMICS SIMULATIONS

KW - GLYCOSYL-ENZYME INTERMEDIATE

KW - TRANSITION-STATE

KW - SUBSTRATE DISTORTION

KW - THERMOTOGA-MARITIMA

KW - CATALYTIC MECHANISM

KW - CANCER

KW - INSIGHTS

KW - HYDROLASES

KW - IDENTIFICATION

UR - http://www.scopus.com/inward/record.url?scp=77249096905&partnerID=8YFLogxK

U2 - 10.1021/ja908908q

DO - 10.1021/ja908908q

M3 - Article

SN - 0002-7863

VL - 132

SP - 1804-+

JO - Journal of the American Chemical Society

JF - Journal of the American Chemical Society

IS - 6

ER -

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

Abstract

Keywords

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