Dr Helge Dorfmueller
The cell wall of Gram-positive bacteria consists of an intricate network of proteins, peptidoglycan, and secondary cell wall structures (SCWS) that are covalently linked to the peptidoglycan. Teichoic or teichuronic acids are typical and well-studied SCWS in Gram-positive bacteria and play an important role in normal cell function and infection. Interestingly, many β-hemolytic streptococcal species appear to lack expression of typical teichoic or teichuronic acid structures and instead express a rhamnose-rich polysaccharide, which comprises approximately half of the cell wall by weight. Historically, expression of these evolutionary conserved glycans underlies classification of β-hemolytic streptococci in Lancefield groups (A, B, C, G...), a feature that is still made use of and applied in contemporary rapid test kits to diagnose and classify streptococcal infections.
The current research focus is on the biosynthesis pathway of the essential sugar nucleotide dTDP-rhamnose. Combinations of methods are applied to conduct functional and structural studies on the enzymes of the dTDP-rhamnose biosynthesis pathway.
This research is conducted in collaboration with:
S. L. van der Beek, A. Zorzoli, E. Çanak, R. N. Chapman, K. Lucas, B. H. Meyer, D. Evangelopoulos, L. P. S. de Carvalho, G.‐J. Boons, H. C. Dorfmueller*, N. M. van Sorge*; (2019, Accepted 12/2018).‘Streptococcal dTDP‐L‐rhamnose biosynthesis enzymes: functional characterization and lead compound identification’, Mol Microbiol.
van der Beek, S. L., Le Breton, Y., Ferenbach, A. T., Chapman, R. N., van Aalten, D. M., Navratilova, I., Boons, G. J., McIver, K. S., van Sorge, N. M. and Dorfmueller, H. C. (2015) GacA is essential for Group A Streptococcus and defines a new class of monomeric dTDP-4-dehydrorhamnose reductases (RmlD). Mol Microbiol
Borodkin, V. S., Schimpl, M., Gundogdu, M., Rafie, K., Dorfmueller, H. C., Robinson, D. A. and van Aalten, D. M. (2014) Bisubstrate UDP-peptide conjugates as human O-GlcNAc transferase inhibitors. Biochem J. 457, 497-502
Dorfmueller, H. C., Ferenbach, A. T., Borodkin, V. S. and van Aalten, D. M. (2014) A structural and biochemical model of processive chitin synthesis. J Biol Chem. 289, 23020-23028
Rao, F. V., Schuttelkopf, A. W., Dorfmueller, H. C., Ferenbach, A. T., Navratilova, I. and van Aalten, D. M. (2013) Structure of a bacterial putative acetyltransferase defines the fold of the human O-GlcNAcase C-terminal domain. Open Biol. 3, 130021
Dorfmueller, H. C., Fang, W., Rao, F. V., Blair, D. E., Attrill, H. and van Aalten, D. M. (2012) Structural and biochemical characterization of a trapped coenzyme A adduct of Caenorhabditis elegans glucosamine-6-phosphate N-acetyltransferase 1. Acta crystallographica. Section D, Biological crystallography. 68, 1019-1029