Miriam P Kötzler

Miriam

Postdoctoral Fellow

 

  •  2009-2012  Dr. rer. nat. – University of Hamburg, Germany (Advisor: Prof. Bernd Meyer)
  • 2004-2009  Dipl. Chem. – University of Hamburg, Germany (M.Sc. equivalent degree, major: Chemistry, minor: Biochemistry)

 

Phone:  604-822-9256
Email:  koetzler(at)chem.ubc.ca

 

RESEARCH INTEREST

Polysaccharides are a valuable and renewable resource for fine chemicals. Effective depolymerization of these highly stable polymers is of high interest for industrial applications. Hence, understanding routes for catalyzed hydrolysis of the glycosidic bond is of fundamental importance to the design of tailored cost-efficient, stable and specific catalysts. Furthermore, the design of specific glycosidase inhibitors as therapeutic drugs demands that our understanding of their catalytic strategies is precise and correct. Enzymes are the world’s most efficient catalysts and glycosidases achieve rate enhancements of up to 1017 fold compared to the uncatalyzed reaction. Two catalytic strategies, i.e., general acid and nucleophilic catalysis are employed by most glycosidases. A significant part of enzymatic proficiency is attributed to synchronization of these two catalytic strategies within the reaction mechanism. Although widely suggested, this hypothesis has been remarkably difficult to prove in model systems or in enzymes themselves. This project aims to probe this synergy experimentally for the first time using a model glycosidase. Therefore, unnatural variants of the enzyme will be prepared by means of synthetic methods. In these synthetic variants, either of the two catalytic strategies is successively attenuated. By measuring the effect of this attenuation on catalytic efficiency, the dependence of one catalytic strategy on the other will be revealed. These kinetic experiments will be combined with physical methods to determine structural features of the altered catalytic pathways. Finally, these data will complement computational simulations of the catalyzed reaction, thereby offering general insights into how glycosides can be hydrolyzed with high efficiency.

 

PUBLICATIONS

  • 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.
  • Kötzler, M.P., Hancock, S. M. and Withers, S. G.. Glycosidases: Functions, Families and Folds. eLS 2014, in press.
  • Kötzler, M. P.; Blank, S.; Bantleon, F. I.; Spillner, E.; Meyer, B., Donor assists acceptor binding and catalysis of human a1,6-fucosyltransferase, ACS Chem. Biol. 2013, 8 (8):1830-40.
  • Schaefer, K. Sindhuwinata, N., Hackl, T., Kötzler, M. P., Niemeyer, F. C., Palcic, M. M. Peters, T., Meyer, B., A non-ionic inhibitor with high specificity for the UDP-Gal donor binding site of human Blood Group B Galactosyltransferase ‑ Design, synthesis and characterization, J. Med. Chem. 2013, 56 (5), 2150-2154
  • Kötzler, M. P.; Blank, S.; Bantleon, F. I.; Spillner, E.; Meyer, B., Donor substrate binding and enzymatic mechanism of human core a1,6-fucosyltransferase (FUT8). Biochim. Biophys. Acta 2012, 1820, 1915–1925.
  • Behnken, H.; Fellenberg, M.; Koetzler, M.; Jirmann, R.; Nagel, T.; Meyer, B., Resolving the problem of chromatographic overlap by 3D cross correlation (3DCC) processing of LC, MS and NMR data for characterization of complex glycan mixtures. Anal. Bioanal. Chem. 2012, 404, 1427–1437.
  • Kötzler, M. P.; Blank, S.; Behnken, H. N.; Alpers, D.; Bantleon, F. I.; Spillner, E.; Meyer, B., Formation of the immunogenic a1,3-fucose epitope: Elucidation of substrate specificity and of enzyme mechanism of core fucosyltransferase A. Insect Biochem. Mol. Biol. 2012, 42 (2), 116-125.