Structure and mechanism of the lipooligosaccharide sialyltransferase from Neisseria meningitidis (2011) J. Biol. Chem. 286: 37237-37248.
In addition to the enzymes involved in the synthesis of the peptidoglycan cell wall, we are also interested in several additional aspects of cell surface biogenesis. One of our projects focuses on the synthesis of wall teichoic acid (WTA). Anionic teichoic acid polymers, along with peptidoglycan, are essential components of the Gram-positive cell wall. Despite being present in roughly equal amounts, very little is known about its synthesis in comparison to peptidoglycan. WTA is anchored to muramic acid of peptidoglycan. Along with lipoteichoic acid (anchored to the membrane) it is proposed to function in virulence, biofilm formation, autolysin regulation, physical protection, cation homeostasis and potential phosphate reservoir. WTA synthesis is catalyzed by different sets of proteins using different mechanisms and in some species results in polymers with differing stereochemistry. WTA is assembled on a lipid scaffold but is eventually transferred to peptidoglycan. WTA polymers contain polyol-phosphate repeating units, the best studied of which are the glycerol-phosphate WTA of B. subtilis 168 and the ribitol-phosphate WTA of S. aureus. We are interested in the various enzymes of the WTA synthetic pathway and have recently published the structure of Staphylococcus epidermidis TagF, a monotopic membrane protein involved in the polymerization of WTA.
We are also interested in the glycosyltransferases, a family of enzymes involved in the biogenesis of cell-surface glycans, especially the subfamily of sialyltransferases. Sialic acid, commonly found at the terminal position of glycoconjugates including glycolipid and glycoproteins, activates a multitude of biological functions through specific recognition of carbohydrate receptors in mammals. We are interested in the mammalian enzymes responsible for the addition of sialic acid to cell-surface glycans. These have been shown to be important in development, the correct functioning of the immune system and also in numerous pathological conditions including tumourgenesis and several neurological conditions. Remarkably, many pathogens have evolved to take advantage of host surface-exposed sialic acids. In bacterial pathogens such as Neisseria meningitidis or Campylobacter jejuni this is evident in an invasion mechanism involving mimicry of either the polysialic acid structure on host neural cell adhesion molecules or the carbohydrate moieties of human gangliosides respectively, which effectively camouflages the bacteria from the human immune system.
Structural and kinetic analysis of substrate binding to the sialyltransferase Cst-II from Campylobacter jejuni (2011) J. Biol. Chem. 286: 35922-35932.
Structure of the bacterial teichoic acid polymerase TagF provides insights into membrane association and catalysis (2010) Nat. Struct. Mol. Biol. 17: 582-589.
Structural insight into mammalian sialyltransferases (2009) Nat. Struct. Mol. Biol. 16: 1186-1188.
The structural basis of glycosidase inhibition by five-membered iminocyclitols: the clan a glycoside hydrolase endoglycoceramidase as a model system (2007) Angew Chem. Int. Ed. Engl. 46: 4474-4476.