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Covalent inhibitors for sugar processing enzymes
The motivation – In humans and other living systems, the addition and removal of sugar molecules to or from functional biomolecules is tightly regulated. Some of the energy that we get from our diet is used to ensure that molecules within the body have the correct sugars attached to them, and then once those molecules are no longer needed, the components – such as the sugars – are recycled to minimize the waste of valuable resources. If any of these processing systems go awry, it can lead to serious consequences for the organism’s health. The aim of this study was to investigate how a newly designed class of covalent inhibitors reacts with biological catalysts or ‘enzymes’ that degrade sugars.
The discovery – Researchers from the Bennet and Britton groups at Simon Fraser University, along with collaborators from the UK and Spain, designed a type of reactive molecule that mimics natural sugars or ‘carbohydrates’ yet is not structurally a sugar. They showed that these molecules have a dramatic ability to inhibit the activity of enzymes that remove sugar units from carbohydrates, which are complex structures made up of multiple sugar units. The targeted carbohydrate processing enzymes are often found in the lysosome, an organelle in human cells that is the centre for recycling these molecular components. The authors demonstrate that their novel group of inhibitors decrease enzyme activity by forming a covalent bond to the enzyme. Over a period of time, however, the enzyme-inhibitor intermediate reacts with water, which frees the enzyme and thus its activity returns to normal.
Its significance – These covalent inhibitors are functionally distinct from most inhibitors, because they do not permanently disable the target enzyme. In contrast, most other inhibitors that covalently bond to an enzyme essentially ‘kill’ it by blocking enzyme reactivation forevermore. Using this new type of inhibitor, researchers can examine cellular responses in more detail; for example, the inhibitor could allow them to observe the effect of a potential drug in a diseased cell by monitoring the cellular response as the activity of a critical carbohydrate processing enzyme decreases and then subsequently returns to baseline levels.
This study was made possible by a team of international collaborators who contributed structural insights (X-ray crystallography expertise from collaborators at the University of St Andrews in Scotland), theoretical modeling expertise (collaborators from Universitat Jaume I in Spain)—which included a six-month intensive research cooperative visit for Canadian graduate student Marco Farren-Dai (funded by grants from NSERC and GlycoNet)—and synthetic and mechanistic chemistry expertise (Simon Fraser University in Canada).
Read the paper – “Revealing the mechanism for covalent inhibition of glycoside hydrolases by carbasugars at an atomic level” by Weiwu Ren, Robert Pengelly, Marco Farren-Dai, Saeideh Shamsi Kazem Abadi, Verena Oehler, Oluwafemi Akintola, Jason Draper, Michael Meanwell, Saswati Chakladar, Katarzyna Świderek, Vicent Moliner, Robert Britton, Tracey M. Gloster & Andrew J. Bennet. Nature Communications 9:3243 (2018). DOI: 10.1038/s41467-018-05702-7
Website article compiled by Jacqueline Watson with Theresa Kitos