丁香园AV

Education

• Ph.D. - University of British Columbia
• CIHR Postdoctoral Fellow - University of California, Berkeley

Affiliations

• Professor of Chemistry
• Professor of Molecular Biology and Biochemistry
• Canada Research Chair in Chemical Biology
• E.W.R. Steacie Memorial Fellow
• Fellow of the Royal Society, College of New Scholars and Scientists
  

Lab Information

• LAB: TASC 2 8060
  
• TEL: 778-782-7015

Research

RESEARCH OBJECTIVE AND BACKGROUND

Researchers from both chemistry and biology backgrounds work together in teams to address interesting fundamental questions as well as translational research focused on major societal health related issues such as neurodegenerative diseases.

Our research focuses on Chemical Glycobiology, which involves using chemical synthesis and biochemistry to develop new chemical tools that enable the wider field to study 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 cell signaling and on to organismal development. The field of glycoscience was recently identified by the National Academy of Sciences as a frontier area of molecular sciences.

THE LABORATORY OF CHEMICAL GLYCOBIOLOGY

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 chemically synthesize substrates and enzyme inhibitors. We use these to investigate the specificities of glycan processing enzymes and use methods in 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 even 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 cancers, Parkinson and Alzheimer disease. Members of the laboratory work collegially 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. The laboratory seeks to use the newest technologies in its research and collaborates extensively with leading experts around the world. Trainees have opportunities to travel to exchange ideas, develop projects, and learn new methods. If you have an interest in joining our group please check out our website: 

Recent Selected Publications:

Cecioni, S., Vocadlo, D.J. Carbohydrate Bis-acetal-Based Substrates as Tunable Fluorescence-Quenched Probes for Monitoring exo-Glycosidase Activity. Journal of the American Chemical Society 2017, 139, 8392-8395

Liu T.-W., Myschyshyn M., Sinclair D.A., Cecioni S., Beja K., Honda B.M., Morin R.D., Vocadlo D.J. Genome-wide chemical mapping of O-GlcNAcylated proteins in Drosophila. Nature Chemical Biology 2017, 13, 161-7.

Perley-Robertson GE, Yadav AK, Winogrodzki JL, Stubbs KA, Mark BL, Vocadlo DJ.* A Fluorescent Transport Assay Enables Studying AmpG Permeases Involved in Peptidoglycan Recycling and Antibiotic Resistance. ACS Chem. Biol., 2016, 11, 2626-35.

Cekic N, Heinonen JE, Stubbs KA, Roth C, He Y, Bennet AJ, McEachern EJ, Davies GJ, Vocadlo DJ.  Analysis of transition state mimicry by tight binding aminothiazoline inhibitors provides insight into catalysis by human O-GlcNAcase. Chem. Sci. 2016, 7, 3742-3750.

Zhu, Y., Liu, T., Eskandari, R., Zandberg, W., Cecioni, S., Vocadlo, D.J.* Cytoplasmic O-GlcNAcylation occurs cotranslationally to stabilize nascent polypeptide chains. Nature Chemical Biology 2015, 11, 319-25.

Yadav AK, Shen D, Shan X, He X, Kermode AR, Vocadlo DJ.  Fluorescence quenched substrates for live cell imaging of human glucocerebrosidase activity.  Journal of the American Chemical Society 2015. 137, 1181-9.

Yuzwa, S.A., Shan, X., Jones, B.A., Zhao, G., Woodward, M.L., Li, X., Zhu, Y., McEachern, E.J., Silverman, M.A., Watson, N.V., Gong, C.-X., Vocadlo, D.J. Pharmacological Inhibition of O-GlcNAcase (OGA) prevents cognitive decline and amyloid plaque formation in bigenic tau/APP mutant mice. Molecular Neurodegeneration 2014; 9, 42.

Yuzwa, S.A., Shan, X., Macauley, M.A., Clark, T., Skorobogatko, Y., Vosseller, K., Vocadlo, D.J. Increasing O-GlcNAc slows neurodegeneration and stabilizes tau against aggregation. Nature Chemical Biology 2012, 8, 393-9.

Gloster, T.M., et al., Hijacking a biosynthetic pathway yields a potent glycosyl transferase inhibitor acting in cells. Nature Chemical Biology 2011, 7, 174-181.