Professor (Joint with Chemistry)
Centre for High-Throughput Biology (CHiBi)
Bristol, 1974, BSc
Bristol (ML Sinnott), 1997, PhD
Alberta (N.B. Madsen and B.D. Sykes), 1978, Postdoctoral
work phone: 6048223402
fax: 6048228869
CHEM A333 or
Vancouver, BC V6T 1Z4

Our interests focus primarily upon enzymes that catalyse glycoside formation and hydrolysis, since these play crucial roles in all areas of biology. Applications of our research (see below) range from the development of new catalysts for industrial processes to the design, synthesis and testing of new therapeutics.

Understanding: Mechanistic studies are the foundation of our program and range from the discovery and analysis of “new” mechanisms by which enzymes catalyse these reactions through to development of a deeper understanding of how the enzymes for which we know the fundamental mechanisms achieve such enormous (107 fold) rate accelerations. The approaches adopted involve a combination of synthetic organic chemistry (synthesis of substrate analogues, inhibitors, etc.), molecular biology (cloning, mutagenesis, etc.,) and biochemistry (enzyme purification, kinetics, labeling, peptide mapping). These are often coupled with collaborative crystallographic and NMR studies of protein/ligand complexes to gain insights into structures, dynamics and electrostatics of the species along the enzyme’s reaction coordinates. We also utilise mass spectrometry for peptide mapping and gas phase studies. Central to our mechanistic studies are the databases CAZY and CAZYPEDIA.

Inhibitors of glycosidases have value both as mechanistic probes and as potential diagnostics and therapeutics. Mechanism-based covalent inhibitors, often based upon fluorosugars, have been designed and used by our lab to prove covalent catalysis, to identify active site residues andto visualize structures of reaction intermediates. These, along with non-covalent inhibitors, are being developed as potential therapeutics in conjunction with B.C.’s Centre for Drug Research and Development (CDRD). Trials are currently underway for new treatments for influenza (neuraminidase inhibition), diabetes (α-amylase inhibition) and lysosomal storage diseases (pharmacological chaperones). These candidates were derived both by design / synthesis and by high-throughput screening of natural product extracts.

Engineering: a particular challenge in glycoscience is the efficient assembly of oligosaccharides and glycoproteins – especially on the large scale. We have generated glycosynthases and glycoligases (engineered glycosidases) for the high-yielding assembly of glycosides. Through application of directed evolution approaches that mimic the process of natural selection, but in the laboratory, we are generating improved versions of these enzymes with activities up to 5000 times higher than their parents. Our involvement in the Centre for High-Throughput Biology (CHiBi) is central to such studies. Students interested in genome-wide and high-throughput chemical biology studies are also alerted to our new Genome Sciences and Technology (GSAT) graduate program.

Selected Publications

To see complete list


Santana, A. G., Tysoe, C. R., Hu, G., Kronstad, J., Goddard-Borger, E., and Withers, S. G. “Fungal glycolipid hydrolase inhibitors and their effect on Cryptococcus neoformans” (2017) ChemBioChem 18, 284-290.

Jongkees, S. A. K., Caner, S., Tysoe, C. R., Brayer, G. D., Withers, S. G. and Suga, H. “Rapid discovery of potent and selective glycosidase-inhibiting de novo peptides” (2017) Cell Chemical Biology. In Press.

Gao, Z., Niikura, M, and Withers, S. G. “Ultrasensitive fluorogenic neuraminidase titration reagents” (2017) Angew. Chemie, In Press, accepted Jan 24 2017.

Gao, Z., Niikura, M, and Withers, S. G. “Ultrasensitive fluorogenic neuraminidase titration reagents” (2017) Angew. Chemie, In Press, accepted Jan 24 2017.

Schalli, M. Wolfsgruber, A., Santana, A. G., Tysoe, C. R., Fischer, R., Thonhofer, M., Withers, S. G. and Stuetz, A. “C-5a-Substituted Validamine Type Glycosidase Inhibitors” (2017) Carbohydr. Res.  440, 1-9.

Strazzulli, A., Cobucci-Ponzano, B, Carillo, S., Bedini, E., Corsaro, M., M., Pocsfalvi, G., Withers, S. G., Rossi, M and Moracci, M. “Introducing transgalactosylation activity into a GH42 -galactosidase” (2017) Glycobiology In Press.


Danby, P.M. and Withers, S.G. “Advances in Enzymatic Glycoside Synthesis” (2016) ACS Chemical Biology 11, 1784-1794.

Morgan, J. L.; McNamara, J. T.; Fischer, M.; Rich, J.; Chen, H. M.; Withers, S. G.; Zimmer, J.  Observing Cellulose Biosynthesis And Membrane Translocation In Crystallo. NATURE 2016, 531, 329–334. doi: 10.1038/nature16966

Thonhofer, M.; Santana, A. G.; Fischer, R.; Gomez, A. T.; Saf, R.; Schalli, M.; Stütz, A.E.; Withers, S. G. 5-Fluoro Derivatives Of 4-Epi-Isofagomine As D-Galactosidase Inhibitors And Potential Pharmacological Chaperones For GM1-Gangliosidosis As Well As Fabry’s Disease.  CARBOHYDRATE RESEARCH 2016, 420, 6-12. doi:10.1016/j.carres.2015.10.009

Mehr, K.; Withers, S. G.  Mechanisms Of The Sialidase And Trans-Sialidase Activities of Bacterial Sialyltransferases From Glycosyltransferase Family 80 (GT80).  GLYCOBIOLOGY 2016, 26, 353-359. doi: 10.1093/glycob/cwv105

Kötzler, M. P.; Withers, S. G.  Proteolytic Cleavage Driven By Glycosylation.  JOURNAL OF BIOLOGICAL CHEMISTRY 2016, 291, 429-434. doi: 10.1074/jbc.C115.698696

Yuen, V. G.; Coleman, J.; Withers, S. G.; Andersen, R. J.; Brayer, G. D.; Mustafa, S.; McNeill, J. H.  Glucose Lowering Effect Of Montbretin A In Zucker Diabetic Fatty Rats.  MOLECULAR AND CELLULAR BIOCHEMISTRY 2016, 411, 473-381. doi: 10.1007/s11010-015-2599-4

McNamara, J. T.; Morgan, J. L.; W Fischer, M.; Rich, J.; Chen, H.; Withers, S. G.; Zimmer, J.  Observing Cellulose Biosynthesis And Membrane Translocation In Crystallo.  NATURE 2016, 529, 329-334. doi: 10.1038/nature16966

Chen, H.; Armstrong, Z.; Hallam, S.J.; Withers, S. G.   Synthesis And Evaluation Of A Series Of 6-Chloro-4-Methylumbelliferyl Glycosides As Fluorogenic Reagents For Screening Metagenomic Libraries For Glycosidase Activity.  CARBOHYDRATE RESEARCH 2016, 421, 33-39. doi: 10.1016/j.carres.2015.12.010

Kwan, D. H.; Jin, Y.; Jiang, J.; Chen, H.; Kötzler, M. P.; Overkleeft, H.S.; Davies, G. J.; Withers, S. G. Chemoenzymatic Synthesis Of 6-Phosphocyclophellitol As A Novel Probe Of 6-Phospho Beta-Glucosidases.  FEBS LETTERS 2016, 590, 461-468. doi: 10.1002/1873-3468.12059

Thonhofer, M.; Weber, P.; Gonzalez Santana, A.; Fischer, R.; Pabst, B. M.; Paschke, E.; Schalli, M.; Stütz, A. E.; Tschernutter, M.; Windischhofer, W.; Withers, S. G.  Synthesis Of C-5a-Chain Extended Derivatives Of 4-Epi-Isofagomine: Notable Beta-Galactosidase Inhibitors And Activity Promotors Of GM1-Gangliosidosis-Related Human Lysosomal Beta-Galactosidase Mutant R201C.  CARBOHYDRATE RESEARCH 2016, 429, 71-80. doi 10.1016/j.carres.2016.03.020

Tysoe, C.T.; Williams, L.K.; Keyzers, R.; Nguyen, N.; Tarling, C.; Wicki, J.; Goddard-Borger, E.D.; Aguda, A.; Perry, S.; Foster, L.J.; Andersen, R.J.; Brayer, G.D.; Withers, S. G.  Potent Human Alpha-Amylase Inhibition By The Beta-Defensin-Like Protein Helianthamide.  ACS CENTRAL SCIENCE 2016, 2, 154-161. doi: 10.1021/acscentsci.5b00399

Caner, S.; Zhang, X.; Jiang, J.; Chen, H.; Nguyen, N. T.; Overkleeft, O.; Brayer, G.D.; Withers, S. G.  Glucosyl Epi-cyclophellitol Allows Mechanism-Based Inactivation And Structural Analysis of Human Pancreatic Alpha-Amylase.  FEBS LETTERS 2016, 590, 1143-1151. doi: 10.1002/1873-3468.12143

Santana, A.G.; Vadlamani, G.; Mark, B. L.; Withers, S. G.  N-Acetyl Glycals Are Tight-Binding And Environmentally Insensitive Inhibitors Of Hexosaminidases. CHEMICAL COMMUNICATIONS 2016, 52, 7943-7946. doi: 10.1039/C6CC02520J

Zoidl, M.; Gonzalez Santana, A.; Torvisco, A.; Tysoe, C.T.; Siriwardena, A.; Withers, S. G.; Wrodnigg, T. M . The Staudinger/aza-Wittig Reaction As Key Step For The Concise Synthesis of 1-C-Alkyl-Iminoalditol Glycomimetics.  CARBOHYDRATE RESEARCH 2016, 429, 62-70. doi: 10.1016/j.carres.2016.04.006

Danby, P.M.; Withers, S.G.   Advances in Enzymatic Glycoside Synthesis.  ACS CHEMICAL BIOLOGY 2016, 11, 1784-1794. doi: 10.1021/acschembio.6b00340

Ma, F.; Fischer, M.; Han, Y.; Withers, S.G.; Feng, Y.; Yang, G.  Substrate Engineering Enabling Fluorescence Droplet Entrapment For IVC-FACS Based Ultrahigh-Throughput Screening.   ANALYTICAL CHEMISTRY 2016. In Press. Accepted August 2016. doi: 10.1021/acs.analchem.6b01712



Sobhanifar, S. ; Worrall, L. James; Gruninger, R. J. ; Wasney, G. A. ; Blaukopf, M. ; Baumann, L. ; Lameignere, E. ; Solomonson, M. ; Brown, E. D. ; Withers, S. G. ; Strynadka, N. C. J. Structure And Mechanism Of Staphylococcus Aureus Tarm, The Wall Teichoic Acid Alpha-Glycosyltransferase. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2015, 112, E576-E585. BibTex


Weck, S. ; Robinson, K. ; Smith, M. R. ; Withers, S. G. Understanding Viral Neuraminidase Inhibition By Substituted Difluorosialic Acids. CHEMICAL COMMUNICATIONS 2015, 51, 2933-2935. BibTex



Jongkees, S. A. K. ; Withers, S. G. Unusual Enzymatic Glycoside Cleavage Mechanisms. ACCOUNTS OF CHEMICAL RESEARCH 2014, 47, 226-235. BibTex


Knott, B. C. ; Momeni, M. Haddad; Crowley, M. F. ; Mackenzie, L. F. ; Goetz, A. W. ; Sandgren, M. ; Withers, S. G. ; Stahlberg, J. ; Beckham, G. T. The Mechanism Of Cellulose Hydrolysis By A Two-Step, Retaining Cellobiohydrolase Elucidated By Structural And Transition Path Sampling Studies. JOURNAL OF THE AMERICAN CHEMICAL SOCIETY 2014, 136, 321-329. BibTex


Duo, T. ; Goddard-Borger, E. D. ; Withers, S. G. Fluoro-Glycosyl Acridinones Are Ultra-Sensitive Active Site Titrating Agents For Retaining Beta-Glycosidases. CHEMICAL COMMUNICATIONS 2014, 50, 9379-9382. BibTex


Jongkees, S. A. K. ; Yoo, H. ; Withers, S. G. Mechanistic Insights From Substrate Preference In Unsaturated Glucuronyl Hydrolase. CHEMBIOCHEM 2014, 15, 124-134. BibTex


Chapanian, R. ; Kwan, D. H. ; Constantinescu, I. ; Shaikh, F. A. ; Rossi, N. A. A. ; Withers, S. G. ; Kizhakkedathu, J. N. Enhancement Of Biological Reactions On Cell Surfaces Via Macromolecular Crowding. NATURE COMMUNICATIONS 2014, 5, 4683. BibTex


Yu, C. – C. ; Hill, T. ; Kwan, D. H. ; Chen, H. – M. ; Lin, C. – C. ; Wakarchuk, W. ; Withers, S. G. A Plate-Based High-Throughput Activity Assay For Polysialyltransferase From Neisseria Meningitidis. ANALYTICAL BIOCHEMISTRY 2014, 444, 67-74. BibTex


Kwan, D. H. ; Withers, S. G. Periplasmic De-Acylase Helps Bacteria Don Their Biofilm Coat. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2014, 111, 10904-10905. BibTex


Zoidl, M. ; Mueller, B. ; Torvisco, A. ; Tysoe, C. ; Benazza, M. ; Siriwardena, A. ; Withers, S. G. ; Wrodnigg, T. M. Concise Synthesis Of C-1-Cyano-Iminosugars Via A New Staudinger/aza Wittig/strecker Multicomponent Reaction Strategy. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 2014, 24, 2777-2780. BibTex


Rempel, B. P. ; Withers, S. G. Phosphodiesters Serve As Potentially Tunable Aglycones For Fluoro Sugar Inactivators Of Retaining Beta-Glycosidases. ORGANIC & BIOMOLECULAR CHEMISTRY 2014, 12, 2592-2595. BibTex


Syson, K. ; Stevenson, C. E. M. ; Rashid, A. M. ; Saalbach, G. ; Tang, M. ; Tuukkanen, A. ; Svergun, D. I. ; Withers, S. G. ; Lawson, D. M. ; Bornemann, S. Structural Insight Into How Streptomyces Coelicolor Maltosyl Transferase Glge Binds Alpha-Maltose 1-Phosphate And Forms A Maltosyl-Enzyme Intermediate. BIOCHEMISTRY 2014, 53, 2494-2504. BibTex


Jongkees, S. A. K. ; Yoo, H. ; Withers, S. G. Mechanistic Investigations Of Unsaturated Glucuronyl Hydrolase From Clostridium Perfringens. JOURNAL OF BIOLOGICAL CHEMISTRY 2014, 289, 11385-11395. BibTex
Tysoe, C. ; Withers, S. G. Fluorinated Mechanism-Based Inhibitors: Common Themes And Recent Developments. CURRENT TOPICS IN MEDICINAL CHEMISTRY 2014, 14, 865-874. BibTex


Buchini, S. ; Gallat, F. – X. ; Greig, I. R. ; Kim, J. – H. ; Wakatsuki, S. ; Chavas, L. M. G. ; Withers, S. G. Tuning Mechanism- Based Inactivators Of Neuraminidases: Mechanistic And Structural Insights. ANGEWANDTE CHEMIE-INTERNATIONAL EDITION 2014, 53, 3382-3386. BibTex


Jongkees, S. A. K. ; Yoo, H. ; Withers, S. G. Mechanistic Insights From Substrate Preference In Unsaturated Glucuronyl Hydrolase. CHEMBIOCHEM 2014, 15, 124-134. BibTex



Stocker, B. L. ; Jongkees, S. A. K. ; Win-Mason, A. L. ; Dangerfield, E. M. ; Withers, S. G. ; Timmer, M. S. M. The `mirror-Image’ Postulate As A Guide To The Selection And Evaluation Of Pyrrolidines As Alpha-L-Fucosidase Inhibitors. CARBOHYDRATE RESEARCH 2013, 367, 29-32. BibTex



Chan, P. H. W. ; Cheung, A. H. ; Okon, M. ; Chen, H. – M. ; Withers, S. G. ; McIntosh, L. P. Investigating The Structural Dynamics Of Alpha-1,4-Galactosyltransferase C From Neisseria Meningitidis By Nuclear Magnetic Resonance Spectroscopy. BIOCHEMISTRY 2013, 52, 320-332. BibTex


Yu, C. – C. ; De Huang, L. -; Kwan, D. H. ; Wakarchuk, W. W. ; Withers, S. G. ; Lin, C. – C. A Glyco-Gold Nanoparticle Based Assay For Alpha-2,8-Polysialyltransferase From Neisseria Meningitidis. CHEMICAL COMMUNICATIONS 2013, 49, 10166-10168. BibTex


Bie, H. ; Yin, J. ; He, X. ; Kermode, A. R. ; Goddard-Borger, E. D. ; Withers, S. G. ; James, M. N. G. Insights Into Mucopolysaccharidosis I From The Structure And Action Of Alpha-L-Iduronidase. NATURE CHEMICAL BIOLOGY 2013, 9, 739+. BibTex


Armstrong, Z. ; Withers, S. G. Synthesis Of Glycans And Glycopolymers Through Engineered Enzymes. BIOPOLYMERS 2013, 99, 666-674. BibTex


Mewis, K. ; Armstrong, Z. ; Song, Y. C. ; Baldwin, S. A. ; Withers, S. G. ; Hallam, S. J. Biomining Active Cellulases From A Mining Bioremediation System. JOURNAL OF BIOTECHNOLOGY 2013, 167, 462-471. BibTex


Caner, S. ; Nguyen, N. ; Aguda, A. ; Zhang, R. ; Pan, Y. T. ; Withers, S. G. ; Brayer, G. D. The Structure Of The Mycobacterium Smegmatis Trehalose Synthase Reveals An Unusual Active Site Configuration And Acarbose-Binding Mode(Dagger). GLYCOBIOLOGY 2013, 23, 1075-1083. BibTex


F. Shaikh, A. ; van Bueren, A. Lammerts; Davies, G. J. ; Withers, S. G. Identifying The Catalytic Acid/base In Gh29 Alpha-L-Fucosidase Subfamilies. BIOCHEMISTRY 2013, 52, 5857-5864. BibTex


Ratananikom, K. ; Choengpanya, K. ; Tongtubtim, N. ; Charoenrat, T. ; Withers, S. G. ; Kongsaeree, P. T. Mutational Analysis In The Glycone Binding Pocket Of Dalbergia Cochinchinensis Beta-Glucosidase To Increase Catalytic Efficiency Toward Mannosides. CARBOHYDRATE RESEARCH 2013, 373, 35-41. BibTex


Ludwiczek, M. L. ; D’Angelo, I. ; Yalloway, G. N. ; Brockerman, J. A. ; Okon, M. ; Nielsen, J. E. ; Strynadka, N. C. J. ; Withers, S. G. ; McIntosh, L. P. Strategies For Modulating The Ph-Dependent Activity Of A Family 11 Glycoside Hydrolase. BIOCHEMISTRY 2013, 52, 3138-3156. BibTex


Rakic, B. ; Rao, F. V. ; Freimann, K. ; Wakarchuk, W. ; Strynadka, N. C. J. ; Withers, S. G. Structure-Based Mutagenic Analysis Of Mechanism And Substrate Specificity In Mammalian Glycosyltransferases: Porcine St3Gal-I. GLYCOBIOLOGY 2013, 23, 536-545. BibTex


Kim, J. – H. ; Resende, R. ; Wennekes, T. ; Chen, H. – M. ; Bance, N. ; Buchini, S. ; Watts, A. G. ; Pilling, P. ; Streltsov, V. A. ; Petric, M. ; Liggins, R. ; Barrett, S. ; McKimm-Breschkin, J. L. ; Niikura, M. ; Withers, S. G. Mechanism-Based Covalent Neuraminidase Inhibitors With Broad-Spectrum Influenza Antiviral Activity. SCIENCE 2013, 340, 71-75. BibTex


Thompson, J. ; Pikis, A. ; Rich, J. ; Hall, B. G. ; Withers, S. G. Alpha-Galacturonidase(S): A New Class Of Family 4 Glycoside Hydrolases With Strict Specificity And A Unique Chev Active Site Motif. FEBS LETTERS 2013, 587, 799-803. BibTex



Rich, J. R. ; Withers, S. G. A Chemoenzymatic Total Synthesis Of The Neurogenic Starfish Ganglioside Llg-3 Using An Engineered And Evolved Synthase. ANGEWANDTE CHEMIE-INTERNATIONAL EDITION 2012, 51, 8640-8643. BibTex


Vocadlo, D. J. ; Withers, S. G. How To Make A Difference: Mechanisms Of Protein And Nucleic Acid Modifying Enzymes Editorial Overview. CURRENT OPINION IN CHEMICAL BIOLOGY 2012, 16, 461-464. BibTex


Withers, S. G. ; Davies, G. J. Glycobiology The Case Of The Missing Base. NATURE CHEMICAL BIOLOGY 2012, 8, 952-953. BibTex


Williams, L. K. ; Li, C. ; Withers, S. G. ; Brayer, G. D. Order And Disorder: Differential Structural Impacts Of Myricetin And Ethyl Caffeate On Human Amylase, An Antidiabetic Target. JOURNAL OF MEDICINAL CHEMISTRY 2012, 55, 10177-10186. BibTex



Reitinger, S. ; Petriv, O. I. ; Mehr, K. ; Hansen, C. L. ; Withers, S. G. Purification And Quantitation Of Bacteriophage M13 Using Desalting Spin Columns And Digital Pcr. JOURNAL OF VIROLOGICAL METHODS 2012, 185, 171-174. BibTex


Shim, J. – H. ; Chen, H. – M. ; Rich, J. R. ; Goddard-Borger, E. D. ; Withers, S. G. Directed Evolution Of A Beta-Glycosidase From Agrobacterium Sp. To Enhance Its Glycosynthase Activity Toward C3-Modified Donor Sugars. PROTEIN ENGINEERING DESIGN & SELECTION 2012, 25, 465-472. BibTex


Pengthaisong, S. ; Chen, C. – F. ; Withers, S. G. ; Kuaprasert, B. ; Cairns, J. R. Ketudat Rice Bglu1 Glycosynthase And Wild Type Transglycosylation Activities Distinguished By Cyclophellitol Inhibition. CARBOHYDRATE RESEARCH 2012, 352, 51-59. BibTex


Michikawa, M. ; Ichinose, H. ; Momma, M. ; Biely, P. ; Jongkees, S. ; Yoshida, M. ; Kotake, T. ; Tsumuraya, Y. ; Withers, S. G. ; Fujimoto, Z. ; Kaneko, S. Structural And Biochemical Characterization Of Glycoside Hydrolase Family 79 Beta-Glucuronidase From Acidobacterium Capsulatum. JOURNAL OF BIOLOGICAL CHEMISTRY 2012, 287, 14069-14077. BibTex


Goddard-Borger, E. D. ; Tropak, M. B. ; Yonekawa, S. ; Tysoe, C. ; Mahuran, D. J. ; Withers, S. G. Rapid Assembly Of A Library Of Lipophilic Iminosugars Via The Thiol-Ene Reaction Yields Promising Pharmacological Chaperones For The Treatment Of Gaucher Disease. JOURNAL OF MEDICINAL CHEMISTRY 2012, 55, 2737-2745. BibTex


Pengthaisong, S. ; Withers, S. G. ; Kuaprasert, B. ; Svasti, J. ; Cairns, J. R. Ketudat The Role Of The Oligosaccharide Binding Cleft Of Rice Bglu1 In Hydrolysis Of Cellooligosaccharides And In Their Synthesis By Rice Bglu1 Glycosynthase. PROTEIN SCIENCE 2012, 21, 362-372. BibTex


Goddard-Borger, E. D. ; Sakaguchi, K. ; Reitinger, S. ; Watanabe, N. ; Ito, M. ; Withers, S. G. Mechanistic Insights Into The 1,3-Xylanases: Useful Enzymes For Manipulation Of Algal Biomass. JOURNAL OF THE AMERICAN CHEMICAL SOCIETY 2012, 134, 3895-3902. BibTex