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Revealing the mechanism for covalent inhibition of glycoside hydrolases by carbasugars at an atomic level

DOI: 10.1038/s41467-018-05702-7 DOI Help

Authors: Weiwu Ren (Simon Fraser University) , Robert Pengelly (University of St Andrews) , Marco Farren-dai (Simon Fraser University) , Saeideh Shamsi Kazem Abadi (Simon Fraser University) , Verena Oehler (University of St Andrews) , Oluwafemi Akintola (Simon Fraser University) , Jason Draper (Simon Fraser University) , Michael Meanwell (Simon Fraser University) , Saswati Chakladar (Simon Fraser University) , Katarzyna Świderek (Universitat Jaume I) , Vicent Moliner (Universitat Jaume I) , Robert Britton (Simon Fraser University) , Tracey M. Gloster (Simon Fraser University) , Andrew J. Bennet (Simon Fraser University)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Communications , VOL 9

State: Published (Approved)
Published: August 2018
Diamond Proposal Number(s): 10071 , 14980

Open Access Open Access

Abstract: Mechanism-based glycoside hydrolase inhibitors are carbohydrate analogs that mimic the natural substrate’s structure. Their covalent bond formation with the glycoside hydrolase makes these compounds excellent tools for chemical biology and potential drug candidates. Here we report the synthesis of cyclohexene-based α-galactopyranoside mimics and the kinetic and structural characterization of their inhibitory activity toward an α-galactosidase from Thermotoga maritima (TmGalA). By solving the structures of several enzyme-bound species during mechanism-based covalent inhibition of TmGalA, we show that the Michaelis complexes for intact inhibitor and product have half-chair (2H3) conformations for the cyclohexene fragment, while the covalently linked intermediate adopts a flattened half-chair (2H3) conformation. Hybrid QM/MM calculations confirm the structural and electronic properties of the enzyme-bound species and provide insight into key interactions in the enzyme-active site. These insights should stimulate the design of mechanism-based glycoside hydrolase inhibitors with tailored chemical properties.

Journal Keywords: Carbohydrates; Enzyme mechanisms; Hydrolases; X-ray crystallography

Subject Areas: Chemistry

Instruments: I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength)

Other Facilities: ESRF