Catalysis, Reactivity and Probe Development in Carbohydrate-Based Chemistry and Biochemistry

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In living systems, such as ourselves, the addition and removal of sugars, which are also known as carbohydrates, is tightly regulated. That is, we use a lot of the energy that we get by eating carbohydrates to ensure that molecules within our bodies have the correct sugars attached to them. If this systems gets "out of whack" then serious diseases can ensue. This NSERC Discovery Grant proposal seeks funds for our research program that is concentrated on three areas of current interest in carbohydrate chemistry and biology.Firstly, we will investigate how a series of crucial enzymes (Nature's catalysts for performing reactions) add sugars to molecules by joining them together with a chemical bond. These enzymes are called sugar transferases and are important because some of them are implicated in many disease states including cancer. We wish to understand how these enzyme work in order that we can design molecules to prevent the transfer of sugars in specific cases, such as in cancer.Secondly, we will continue our efforts in making reactive non-sugar molecules, which we have designed to imitate carbohydrates. To date, our molecules have shown a dramatic ability to decrease (or inhibit) the activity of enzymes that remove sugars from carbohydrate chains such as those found in starch. Our new inhibitors will be tested in situations were enzyme activity is greater than it should be in normal individuals. That is, if we can lower the enzyme activity, by administering our molecules, to that of a non-diseased individual (normal level) then these compounds are potential therapeutic agents.Lastly, we will use the latest techniques in modern molecular biology to develop new enzyme catalysts. In this endeavour we are using our experience with an enzyme (called a sialidase) that regulates several critical processes of self-recognition, which is important since we don't want our immune system to attack us. We have over ten years of experience with sialidase enzymes and will use this experience to modify the enzyme so that it can be used to test for abnormalities in the carbohydrates that are attached to various cells. Such modified enzymes will be very useful tools for researchers who are interested in cell to cell communication, for example, a cell has to know whether its neighbor is also a Human cell. Our modified enzymes can also be used to test for various types of cancer as many cancer cells show an abnormal array of carbohydrates on their surfaces.