Structural and Fragment approaches to the modulation of O-GlcNAc in cells

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The function of many of the large macromolecules that control biological processes in a cell can be changed by chemical modification with a sugar called O-GlcNAc. Two enzymes control this chemical modification: a transferase (OGT) that adds the sugar to the protein and a hydrolase (OGA) which removes it. This addition of a sugar is analogous to other mechanisms of control in the cell - such as phosphorylation where a phosphate is added (with a kinase) or removed (with a phosphatase). A great deal is known about how phosphorylation occurs and its consequences on the cell - indeed, many of the more recent drugs that have been discovered are kinase inhibitors that have an impact in conditions such as cancer. However, the O-GlcNAc modification has only recently been discovered and we are only now beginning to discover what happens to cells when the pattern of modification is changed. One recent discovery is that the O-GlcNAc modification has a role in maintaining healthy neurones, and disruption has some impact on neurodegenerative diseases such as Alzheimer's. The aim of our research is to understand more about what these enzymes, OGA and OGT, look like and how they work. This knowledge will be of interest in its own right, but it also provides information which can be used to design small molecule compounds that can bind to the enzymes and change their activity - interestingly, we can both increase and decrease how quickly the enzymes work. It is difficult to find such small molecules by trial and error. One new technique that has been developed recently is the method of fragment-based discovery. Instead of having to find the complete molecule that fits the binding site, this approach begins by identifying smaller pieces of molecule that bind. If the way in which these small fragments bind can be understood, then the chemist can design changes that merge or grow these fragments into the larger compound with the correct properties. We will use these methods to discover small molecules that change the activity of OGA and OGT. These can then be added to cells to see what effect changing the O-GlcNAc has on the way the cells behave. The principle aim is to understand the effect on cell biology, though the compounds may provide a starting place for drug design.