Professor, Canada Research Chair Tier II
- Office: C9066
- Tel: 778-782-3530
- Fax: 778-782-3765
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- Lab: TASC 2 8060
- Tel: 778-782-7015
- Ph.D. - University of British Columbia
- CIHR Postdoctoral Fellow - University of California, Berkeley
- Professor of Chemistry
- Professor of Molecular Biology and Biochemistry
- Canada Research Chair in Chemical Glycobiology
- E.W.R. Steacie Memorial Fellow
The Laboratory of Chemical Glycobiology
Chemical glycobiology involves the use of chemistry and biochemistry to develop chemical tools that enable studying the roles of carbohydrates in biology. Contrary to popular belief, carbohydrates are not simply energy sources. They play many essential roles in cell and organismal biology. Indeed, all cells from every kingdom of life are coated by carbohydrates that function to communicate the inner state of the cell to the outside world. Various different monosaccharide building blocks are known and these are linked together by enzymes to form chain-like structures known as glycans. These glycans are often found as part of conjugates with proteins and lipids and are displayed on the surface of cells where they are serve as ligands of proteins found on other cells. The glycan structures present within these glycoconjugates can be remodeled by enzymes that prune and sculpt these structures. These regulated glycan structures are being uncovered as critical factors in health and disease, playing roles in processes ranging from inflammation to development.
The laboratory of chemical glycobiology headed by Dr. Vocadlo is engaged in the study of; (i) carbohydrate processing enzymes that act on glycoconjugates, (ii) the development of chemical tools to both perturb the action of these enzymes as well as to monitor glycoconjugates, and (iii) the use of these chemical tools to gain new understanding as to how these enzymes and glycoconjugates regulate cellular and organismal physiology. To realize these aims we study the structures of glycoconjugates using various analytical approaches. We also chemically synthesize substrates to investigate the specificities of glycan processing enzymes and use the methods of physical organic chemistry and biochemistry to understand how such enzymes work. Insights gained through such studies are used to synthesize chemical probes of these enzymes, with a focus on enzyme inhibitors. These probes are validated in vitro, in cells, and in vivo. A key objective of the laboratory is to create probes of glycan processing enzymes that can be used to evaluate the roles of interesting glycoconjugates in diseases such as cancer and Alzheimer disease. Members of the laboratory work as a team to address new problems in the area of glycobiology and come from different backgrounds including, for example, chemistry, biochemistry, and cell biology.
Gloster, T. M. and Vocadlo, D.J. Glycan processing enzyme inhibitors; enabling tools for glycobiology. Nature Chemical Biology. 2012, 8, 683-94.
Yuzwa, S.A. and Vocadlo, D.J. O-GlcNAc and neurodegeneration: biochemical mechanisms and potential roles in Alzheimer's disease and beyond. Chemical Society Reviews 2014, Published on-line DOI: 10.1039/C4CS00038B.
Cecioni, S., Vocadlo, D.J. Tools for probing and perturbing O-GlcNAc in cells and in vivo. Current Opinion in Chemical Biology 2013, 17, 719-28.
The O-GlcNAc post-translational modification
One current area of interest is the modification of serine and threonine residues of nuclear and cytoplasmic proteins with N-acetylglucosamine residues in what is known as the O-GlcNAc post-translational modification. This modification is abundant within all multicellular eukaryotes and its levels are maintained by only two enzymes. A glycosyltransferase known as O-GlcNAc transferase (OGT) acts to install O-GlcNAc at sites of modification. A glycoside hydrolase known as O-GlcNAcase (OGA) acts to remove this modification. The coordinated action of these enzymes results in the cycling of O-GlcNAc on proteins. Levels of O-GlcNAc have also been shown to fluctuate in response to the availability of glucose to cells as well as to be able to influence serine and threonine phosphorylation. O-GlcNAc is therefore a nutrient responsive post-translational modification that is able to modulate phosphorylation within signaling pathways. Accordingly, O-GlcNAc has been implicated in various disease states including cancer and neurodegeneration.
O-GlcNAc plays fundamental roles in biology as was recently uncovered in a collaborative effort with the laboratories of Drs. Sinclair, Honda, and Brock, where it was found that OGT is a polycomb group protein (PcG), which are protein regulators of gene expression. Owing to the interest in the basic roles of O-GlcNAc we have carried out detailed studies of both OGA and OGT. We continue to explore the catalytic mechanism of these enzymes and have developed inhibitors of both of these enzymes. We generated the first highly selective inhibitors of OGA and showed these cross the blood brain barrier to increase O-GlcNAcylation in the brain. Using these tools we have proposed OGA as a potential therapeutic target for the treatment of Alzheimer disease. Recently we demonstrated in a transgenic tau model, that OGA inhibition decreases tau aggregation and tau-driven neurodegeneration. More recently, we have gained insights into the glycosyltransferase OGT and have developed a Trojan horse strategy to inhibit the OGT in cells with single digit micromolar potency. We are continuing our research in the area, developing and refining chemical probes to determine their generality, as well as using these powerful reagents to study the basic biological roles of O-GlcNAc. We collaborate extensively with researchers world-wide to gain insight into the functions of O-GlcNAc. Among others, we have developed collaborations with structural biologists Dr. Davies at the University of York, Dr. Suzanne Walker at Harvard, and the structural genomics consortium (SGC) at the University of Toronto.
Lazarus, M.B., et al Structural snapshots define the mechanism of O-GlcNAc transferase. Nat. Chem. Biol., 2012, 8, 966-968.
Yuzwa, S.A., et al., Increasing O-GlcNAc slows neurodegeneration and stabilizes tau against aggregation. Nat. Chem. Biol. 2012, 8, 393-9.
Gloster, T.M., et al., Hijacking a biosynthetic pathway yields a potent glycosyl transferase inhibitor acting in cells. Nat. Chem. Biol. 2011, 7, 174-181.
Sinclair, D.A.R., et al., Drosophila O-GlcNAc transferase (OGT) is encoded by the Polycomb group (PcG) gene, super sex combs (sxc). Proc. Natl. Acad. Sci. USA. 2009, 106, 13427-33.
Yuzwa, S.A., et al., A potent mechanism-inspired O-GlcNAcase inhibitor that blocks phosphorylation of Tau in vivo. Nat. Chem. Biol. 2008, 4, 483-490.
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