Dissecting conformational contributions to glycosidase catalysis and inhibition

https://doi.org/10.1016/j.sbi.2014.06.003Get rights and content
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Highlights

  • The conformational itinerary describes the changes in sugar shape during catalysis.

  • Stereoelectronic requirements for glycoside hydrolysis are discussed.

  • Major and emerging approaches to define conformational itineraries are reviewed.

  • New assignments of glycosidase conformational itineraries are summarized.

Glycoside hydrolases (GHs) are classified into >100 sequence-based families. These enzymes process a wide variety of complex carbohydrates with varying stereochemistry at the anomeric and other ring positions. The shapes that these sugars adopt upon binding to their cognate GHs, and the conformational changes that occur along the catalysis reaction coordinate is termed the conformational itinerary. Efforts to define the conformational itineraries of GHs have focussed upon the critical points of the reaction: substrate-bound (Michaelis), transition state, intermediate (if relevant) and product-bound. Recent approaches to defining conformational itineraries that marry X-ray crystallography of enzymes bound to ligands that mimic the critical points, along with advanced computational methods and kinetic isotope effects are discussed.

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