Figure: Structural analysis reveals the mechanism of a cyclopropyl carbasugar inhibitor binding to a glycoside enzyme as a covalent enzyme inhibitor. Left panel: the inhibitor (shown in green) sits in the enzyme’s active site; Middle panel: the enzyme reacts rapidly with the inhibitor to form a covalent bond (the enzyme’s reacting amino acid residue is shown in the upper left as an aqua-coloured structure), in essence, ‘putting the enzyme to sleep’; Right panel: the enzyme can slowly reactivate by reversing the reaction.

Rational design of inhibitors for sugar processing enzymes

The motivationCarbohydrates (i.e., sugars) are found throughout Nature and do much more than provide energy for daily life; e.g., sugars on the surface of our cells help the body recognize the cells as being "us".  Critical to this control system, sugars can be added and removed efficiently from cellular components by enzymes in the cell.  An ongoing challenge for researchers is to obtain very specific information about the structure and actions of various types of enzymes (e.g., the glycoside hydrolase class of enzymes are responsible for removing sugars from cellular proteins) and use that knowledge to design compounds that selectively inhibit those particular enzymes.

The discovery – In their recent Angewandte “Very Important Paper”, SFU researchers describe the synthesis of a novel sugar-like compound – a cyclopropyl carbasugar – that displays customizable reactivity with glycoside hydrolase enzymes.  They treated the enzyme with this new inhibitor and examined in detail the structure of the inhibited enzyme.  Based on the results, they described for the first time the sequence of changes that occur to this enzyme's structure as it reacts with a sugar molecule – in this case, their carbasugar, which ‘looks’ like a normal sugar to the enzyme. In particular, they uncovered the fine details of the reaction mechanism, which goes through a cycle of inactivation followed by reactivation of the enzyme; this novel compound is an example of a mechanism-based covalent enzyme inhibitor.

Its significance – Beyond the immediate focus of their study, the rational method used by these scientists provides a basis for designing mechanism-based covalent inhibitors that are applicable to other sugar processing enzymes, and this knowledge will lead to a better understanding of carbohydrate metabolism.

Read the paper“Structural Snapshots for Mechanism-Based Inactivation of a Glycoside Hydrolase by Cyclopropyl Carbasugars” by C. Adamson, R. J. Pengelly, S. Shamsi Kazem Abadi, S. Chakladar, J. Draper, R. Britton, T. M. Gloster, A. J. Bennet. Angew. Chem. Int. Ed. 55:14978–14982 (2016). DOI: 10.1002/anie.201607431

Website article compiled by Jacqueline Watson with Theresa Kitos