Withers, Stephen

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

Office: CHEM A333 or NETWORKS OF CENTRES OF EXCELLENCE
Office Phone: 604–822–3402
Fax: 604–822–8869
E-mail: withers@chem.ubc.ca
Website: https://www.msl.ubc.ca/people/dr-stephen-withers/

Research Interest

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.

Publications

Comprehensive List

Selected Publications

  1. Gao, Z., Ovchinnikova, O.G., Huang, B., Liu, F., Williams, D.E., Andersen, R.J. Lowary, T.L., Whitfield, C. and Withers, S.G. “A High-Throughput “FP-Tag” Assay for the Identification of Glycosyltransferase Inhibitors” (2019) J Am Chem Soc In Press, provisionally accepted Jan 2019
  2. Brockerman, J.A., Okon, M., Withers, S.G. and McIntosh, L.P. “The pKa values of the catalytic residues in the retaining glycoside hydrolase T26H mutant of T4 lysozyme” (2019) Protein Science In Press, accepted Dec. 2018
  3. Tegl, G., Hanson, J., Kwan, D.H., Santana, A.G. and Withers, S.G. “Facile formation of ß-thioGlcNAc linkages to thiol-containing sugars, peptides, and proteins using a mutant GH20 hexosaminidase” (2019) Angew Chemie In Press, accepted Dec 13th 2018.
  4. Vickers, C., Liu, F., Abe, K., Salama-Alber, O., Jenkins, M., Springate, C.M.K., Burke, J.E., Withers, S.G. and Boraston, A.B. “Endo-fucoidan hydrolases from glycoside hydrolase family 107 display structural and mechanistic similarities to ?-L-fucosidases from glycoside hydrolase family 29” (2018) J. Biol. Chem. 293, 18296-18308
  5. Du, Ting; Buenbrazo, Nakita; Kell, Laura; Rahmani, Sadia; Sim, Lyann; Withers, Stephen; DeFrees, Shawn; Wakarchuk, Warren “A bacterial expression platform for production of therapeutic proteins containing human-like O-linked glycans.” (2019) Cell Chemical Biology, In Press, Accepted Sept 2018.
  6. Perrella, N.N., Withers, S.G., and Lopes, A.R.“Identity and role of the non-Conserved Acid/Base Catalytic residue in the GH29 fucosidase from the spider Nephilingis cruentata” (2018) Glycobiology, 28, 925-932.
  7. Tysoe, C.R. and Withers, S.G. “Structural dissection of helianthamide reveals the basis of its potent inhibition of human pancreatic ?-amylase”. (2018) Biochemistry 57, 5384-5387.
  8. Gao, Z., Thompson, A., Paulson, J and Withers, S.G. “Proximity Ligation-Based Fluorogenic Imaging Agents for Neuraminidases” (2018) Angew. Chemie 57, 13538-13541.
  9. Nasseri, S. A., Betschart, L., Opaleva, D., Rahfeld, P. and Withers, S.G. “A mechanism based approach to screening metagenomic libraries for unconventional glycosidases” (2018) Angew. Chemie 57, 11359-11364.
  10. Chen, H and Withers, S.G. “Synthesis of azido-deoxy and amino-deoxy glycosides and glycosyl fluorides for screening of glycosidase libraries and assembly of substituted glycosides” (2018) Carbohydr. Res. 467, 33-34.
  11. Irmisch, S., Jo, S., Roach, C., Jancsik, S., Yuen, M., Madilao, L., O’Neil-Johnson, M., Williams,  R., Withers, S.G. and Bohlmann, J. “Discovery of UDP-Glycosyltransferases and BAHD-Acyltransferases in the Biosynthesis of the Anti-Diabetic Plant Metabolite Montbretin A” (2018) The Plant Cell, 30, 1864-1886.
  12. Kötzler, M.P., Robinson, K., Chen, H-M., Okon, M., McIntosh, L.P. and Withers, S.G. “Modulating the nucleophile of a glycoside hydrolase through site-specific incorporation of fluoroglutamic acids (2018) J. Am. Chem. Soc. 140, 8268-8276.
  13. Armstrong, Z., Mewis, K., Liu, F., Scofield, M., Durno, W., Chen, H., Mehr, K., Hanson, N., Konwar, K., Withers, S.G., and Hallam, S.J. “Metagenomics reveals functional synergy and novel polysaccharide utilization loci in the Castor canadensis fecal microbiome” (2018) ISME J 12, 2757-2769.  DOI https://doi.org/10.1038/s41396-018-0215-9
  14. Blaukopf, M., Worrall, L., Kosma, P., Strynadka, N.C.J. and Withers, S.G. “Insights into heptosyltransferase I catalysis and inhibition through the structure of its ternary complex” (2018) Structure 26, 1399-1407.
  15. Weber, P., Nasseri, S.A., Pabst, B.M., Gomez, A.T., Müller, P., Paschke, E. Tschernutter, M., Windischhofer, W., Withers, S.G., Wrodnigg, T.M., and Stütz, A.E. “Potent GH20 N-Acetyl-beta-D-hexosaminidase inhibitors: N-Substituted 4-acetamido-5-amino- 1-hydroxymethyl-cyclopentanediols” (2018) Molecules 23, 708.
  16. Hettle, A. G., Vickers, A. C., Robb, C.S., Liu, F., Withers S.G., Hehemann, J-H., and Boraston A.B. “The molecular basis of polysaccharide sulfatase activity and a nomenclature of catalytic subsites in this class of enzyme” (2018) Structure 26, 747-758.
  17. Smirnova, I., Kasho, V., Jiang, X., Chen, H.-M., Withers, S.G. and Kaback, R.H. “Oversized galactosides as a probe for conformational dynamics in LacY” (2018) PNAS 115, 4146-4151.
  18. Macdonald, S.S., Patel, A., Larmour, V.L.C., Morgan-Lang, C., Hallam, S.J., Mark, B.L., and Withers, S.G. “Structural and mechanistic analysis of a Beta-glucoside phosphorylase identified by screening a metagenomic library” (2018) J Biol Chem 293, 3451-3467.
  19. Duo, T., Robinson, K., Greig, I., Chen,  H., Patrick, B.O. and Withers, S.G. “Remarkable reactivity differences between glucosides with identical leaving groups”(2017) J Am. Chem. Soc 8, 139, 15994-15999.
  20. Centko, R.M., Ratnaweera, P.B., Tysoe, C.R., Withers, S.G., Dilip De Silva, E. and Andersen,R.J. “Alpha-glucosidase and alpha-amylase inhibiting thiodiketopiperazines from the endophytic fungus Setosphaeria rostrata isolated from the medicinal plant Costus speciosus in Sri Lanka” (2017) Phytochemistry Letters 22, 76-80.
  21. Saxena, H., Hsu, B., de Asis, M., Zierke, M, Sim, L., Withers, S.G. and Wakarchuk, W.,  “Characterization of a Thermostable Endoglucanase from Cellulomonas fimi ATCC484” (2018) Biochemistry and Cell Biology 96, 68-76.
  22. 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. DIO: 10.1002/cbic.201600538
  23. 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 24, 381-390.
  24. Gao, Z., Niikura, M, and Withers, S. G. “Ultrasensitive fluorogenic neuraminidase titration reagents” (2017) Angew. Chemie, 56, 6112-6116.
  25. 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.
  26. 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 27, 425-437.
  27. Kuatsjah, E., Chen, H., Withers, S. G. and Eltis, L.D. “Characterization of an extradiol dioxygenase involved in the catabolism of lignin-derived biphenyl” (2017) FEBS Letts 591, 1001-1009.
  28. Lebl, R., Thonhofer, M., Tysoe, C.R. Pabst, B.M., Schalli, M., Weber, P., Paschke, E., Tschernutter, M., Windischhofer, W. and Withers, S. G. “A Morita-Baylis-Hillman based route to C-5a-chain-extended 4-epi-isofagomine type glycosidase inhibitors” (2017) Carbohydr. Res. 442, 31-40.
  29. Kötzler, M.P., McIntosh, L.P. and Withers, S. G. “Refolding the unfoldable: A systematic approach for renaturation of Bacillus circulans xylanase” (2017) Protein Science 26, 1555-1563.
  30. Lizak, C., Worrall, L.J.,  Baumann, L., Fleiderer, M., Volkers, G., Sun, T., Sim, L., Wakarchuk, W.W., Withers, S. G. and Strynadka, N.C.J. “X-ray crystallographic structure of a bacterial polysialyltransferase provides insight into the biosynthesis of capsular polysialic acid” (2017) Scientific Reports, 7, 5842.
  31. Schalli, M., Weber P., Tysoe, C., Pabst, B.M., Thonhofer, M., Paschke, E., Stütz, A.E., Tschernutter, M., Windischhofer, W., and Withers, S. G. “N-Substituted 5-amino-1-hydroxymethyl-cyclopentanetriols: a new family of activity promotors for a GM1-gangliosidosis-related human lysosomal ?-galactosidase mutant” 2017) Carbohydr. Res. 443, 15-22.
  32. Li, Z., Fischer, M., Satkunarajah, M., Zhou, D., Withers, S. G. and Rini, J. M. “Structural basis of Notch O-glycosylation by mammalian protein-O-glucosyltransferase 1 (POGLUT1)” (2017) Nature Communications, 8:185, 1-12.
  33. Danby P.M. and Withers, S. G. “Glycosyl Cations versus Allylic Cations in Spontaneous and Enzymatic Hydrolysis” (2017) J. Am. Chem. Soc. 139, 10629-10632.
  34. Armstrong, Z., Rahfeld, P. and Withers, S. G. “Discovery of New Glycosidases from Metagenomic Libraries” (2017) Methods Enzymol. 597, 3-23.
  35. Schalli, M., Weber P., Tysoe, C., Pabst, B.M., Thonhofer, M., Paschke, E., Stütz, A.E., Tschernutter, M., Windischhofer, W., and Withers, S. G. “N-Substituted 5-amino-1-hydroxymethyl-cyclopentanetriols: a new family of activity promotors for a GM1-gangliosidosis-related human lysosomal beta-galactosidase mutant” (2017) Carbohydr. Res. 443, 15-22.
  36. Mageroy, M.H., Jancsik, S., Yuen, M.M.S, Fischer, M., Withers, S. G., Paetz, C., Schneider, B., MacKay, J., and Bohlmann, J. “Conifer defense against insects: A white spruce family-1 UGT involved in acetophenone metabolism” (2017) Plant Physiol. 175, 641-651.
  37. Duo, T., Robinson, K., Greig, I., Chen,  H., Patrick, B.O. and Withers, S.G. “Remarkable reactivity differences between glucosides with identical leaving groups” (2017) J Am. Chem. Soc 8, 139, 15994-15999.
  38. Wakarchuk, W., Saxena, H., Hsu, B., de Asis, M., Zierke, M, Sim, L. and Withers, S.G. “Characterization of a Thermostable Endoglucanase from Cellulomonas fimi ATCC484”  (2017) Biochemistry and Cell Biology In Press.
  39. Centko, R.M., Ratnaweera, P.B., Tysoe, C.R., Withers, S.G., Dilip De Silva, E. and Andersen,R.J. “Alpha-glucosidase and alpha-amylase inhibiting thiodiketopiperazines from the endophytic fungus Setosphaeria rostrata isolated from the medicinal plant Costus speciosus in Sri Lanka”(2017) Phytochemistry Letters 22, 76-80.
  40. Danby, P.M. and Withers, S.G. “Advances in Enzymatic Glycoside Synthesis” (2016) ACS Chemical Biology 11, 1784-1794.
  41. 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
  42. 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
  43. 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
  44. 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
  45. 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
  46. 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
  47. 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
  48. 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
  49. 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
  50. 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
  51. 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
  52. 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
  53. 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
  54. Danby, P.M.; Withers, S.G.   Advances in Enzymatic Glycoside Synthesis.  ACS CHEMICAL BIOLOGY 2016, 11, 1784-1794. doi: 10.1021/acschembio.6b00340
  55. 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
  56. Solmaz Sobhanifar, Liam J. Worrall, Robert J. Gruninger, Gregory A. Wasney, Markus Blaukopf, Lars Baumann, Emilie Lameignere, Matthew Solomonson, Eric D. Brown, Stephen G. Withers, Natalie C. J. Strynadka. “An intimate look at the structure and mechanism of Staphylococcus aureus TarM, the wall teichoic acid α-glycosyltransferase” (2015)  PNAS 112, E576-E585.
  57. Yun-Bin Han, Lie Wu, Jamie R. Rich, Feng-Tao Huang, Stephen G. Withers, Yan Feng and Guang-Yu Yang. “Comprehensive Characterization of Sphingolipid Ceramide N-deacylase using HPLC Assays” (2015) Appl Microbiol Biotechnol, 99, 6715-6726.
  58. David H. Kwan, Iren Constantinescu, Rafi Chapanian, Melanie A. Higgins, Eric Samain, Aslasdair B. Boraston, Jayachandran N. Kizhakkedathu, and Stephen G. Withers “Towards efficient enzymes for the generation of universal blood through structure-guided directed evolution” (2015) J. Am. Chem. Soc. 137, 5695-5705.
  59. Guang-Yu Yang, Caishun Li, Michael Fischer, Christopher Cairo, Yan Feng and Stephen G. Withers. “A FRET Probe for Cell-based Imaging of Ganglioside-degrading Enzyme Activity and High-throughput Screening”. (2015) Angew Chemie 54, 5479-5483.
  60. Leslie K.  Williams,  Xiaohua Zhang, Sami Caner, Christina Tysoe, Nham T. Nguyen, Jacqueline Wicki, David E. Williams, John Coleman, John McNeill, Violet Yuen, Raymond J. Andersen, Stephen G. Withers, Gary D. Brayer.  “The amylase inhibitor montbretin A reveals a new glycosidase inhibition motif” (2015) Nature Chem. Biol. 11, 691-6.
  61. Stefan Weck, Kyle Robinson, Matthew R. Smith and Stephen G. Withers “Understanding viral neuraminidase inhibition by substituted difluorosialic acids”. (2015) Chem. Commun. 51, 2933-2935
  62. Spencer S. Macdonald, Markus Blaukopf, and Stephen G. Withers. “N-Acetylglucosaminidases from AZy Family GH3 Are Really Glycoside Phosphorylases, Thereby Explaining Their Use of Histidine as an Acid/Base Catalyst in Place of Glutamic Acid” (2015). J. Biol. Chem. 290, 4887-4895.
  63. Andreas Gesell, Markus Blaukopf, Lina Madilao, Macaire M. S. Yuen,  Stephen G. Withers, Jim  Mattsson, John H.  Russell, Joerg Bohlmann.  “The gymnosperm cytochrome P450 CYP750B1 catalyzes stereospecific monoterpene hydroxylation of (+)-sabinene in thujone biosynthesis in Thuja plicata” (2015) Plant Physiology 168, 94-106.
  64. Gesa Volkers, Liam J. Worrall, David H. Kwan, Ching-Ching Yu, Lars Baumann, Emilie Lameignere, Nichollas E. Scott, Leonard J. Foster, Stephen G. Withers, Natalie C.J. Strynadka. “Structure of human ST8SiaIII sialyltransferase provides insight into cell surface polysialylation” (2015) Nature Struct Mol Biol. 22, 627-635.
  65. Steve Arns, Jason Tan, Sharon Sun, Adam Galey, Jay Paquette, Elyse Bourque, Stephen G. Withers, Richard Liggins. “Assessing the Oral Bioavailability of Difluorosialic Acid Prodrugs, Potent Viral Neuraminidase Inhibit, Using A Snapshot PK Screening Assay” (2015) Bioorg Med Chem Lett, 25, 2505-2509.
  66. David H Kwan, Sabrina Ernst, Miriam Koetzler.  “Chemoenzymatic Synthesis of a Type 2 Blood Group A tetrasaccharide and Development of High-Throughput Assays Enables a Platform for Screening Blood Group Antigen-Cleaving Enzymes” (2015) Glycobiology, 8, 808-811.
  67. Ching-Ching Yu and Stephen G. Withers. “Recent Developments in Enzymatic Synthesis of Modified Sialic Acid Derivatives” (2015) Adv Synth Catal 357, 1633-1654.
  68. Sheldon Tai, O Agafitei, Z Gao, R Liggins, M Petric, Stephen G. Withers, M Niikura. “Difluorosialic Acids, Potent Novel Influenza Virus Neuraminidase Inhibitors, Induce Fewer Drug Resistant Neuraminidase Mutations than does Oseltamivir” (2015) Virus Research 210, 126-132.
  69. Jongkees, S. A. K. ; Withers, S. G. Unusual Enzymatic Glycoside Cleavage Mechanisms. ACCOUNTS OF CHEMICAL RESEARCH 2014, 47, 226-235. BibTex
  70. Withers, S. G. Discovery And Improvement Of Novel Glycosidases Through Metagenomics And Directed Evolution. GLYCOBIOLOGY 2014, 24, 1086. BibTex
  71. 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
  72. 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
  73. Jongkees, S. A. K. ; Yoo, H. ; Withers, S. G. Mechanistic Insights From Substrate Preference In Unsaturated Glucuronyl Hydrolase. CHEMBIOCHEM 2014, 15, 124-134. BibTex
  74. 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
  75. 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
  76. 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
  77. 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
  78. 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
  79. 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
  80. 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
  81. Tysoe, C. ; Withers, S. G. Fluorinated Mechanism-Based Inhibitors: Common Themes And Recent Developments. CURRENT TOPICS IN MEDICINAL CHEMISTRY 2014, 14, 865-874. BibTex
  82. 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
  83. Jongkees, S. A. K. ; Yoo, H. ; Withers, S. G. Mechanistic Insights From Substrate Preference In Unsaturated Glucuronyl Hydrolase. CHEMBIOCHEM 2014, 15, 124-134. BibTex
  84. 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
  85. Shim, J. – H. ; Withers, S. G. Improvement Of The Expression Level Of Beta-Glucosidase From Agrobacterium Sp In Escherichia Coli By Rare Codon Optimization. FOOD SCIENCE AND BIOTECHNOLOGY 2013, 22, 269-273. BibTex
  86. 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
  87. 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
  88. 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
  89. Armstrong, Z. ; Withers, S. G. Synthesis Of Glycans And Glycopolymers Through Engineered Enzymes. BIOPOLYMERS 2013, 99, 666-674. BibTex
  90. 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
  91. 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
  92. 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
  93. 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
  94. 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
  95. 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
  96. 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
  97. 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
  98. 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
  99. 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
  100. Withers, S. G. ; Davies, G. J. Glycobiology The Case Of The Missing Base. NATURE CHEMICAL BIOLOGY 2012, 8, 952-953. BibTex
  101. 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
  102. Yip, V. L. Y. ; Withers, S. G. Identification Of Tyr241 As A Key Catalytic Base In The Family 4 Glycoside Hydrolase Bgit From Thermotoga Maritima. BIOCHEMISTRY 2012, 51, 8464-8474. BibTex
  103. Chan, P. H. W. ; Weissbach, S. ; Okon, M. ; Withers, S. G. ; McIntosh, L. P. Nuclear Magnetic Resonance Spectral Assignments Of Alpha-1,4-Galactosyltransferase Lgtc From Neisseria Meningitidis: Substrate Binding And Multiple Conformational States. BIOCHEMISTRY 2012, 51, 8278-8292. BibTex
  104. 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
  105. 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
  106. 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
  107. 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
  108. 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
  109. 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
  110. 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