Specialization

Biochemistry and Molecular Biology

Focus of research

Our research focuses on the biosynthesis and breakdown of one of the three most important structural components of the fungal cell wall, alpha-glucan. Because human fungal pathogens, such as the yeast Cryptococcus neoformans and the filamentous fungus Aspergillus fumigatus, depend on an intact cell wall for survival, the enzymes responsible for its synthesis form ideal targets for the rational design of antifungal drugs.

Antifungal strategies against fungal pathogens have been hampered by the fact that fungi, like humans, are eukaryotes and thus hold their general metabolism in common with humans. Fungi do, however, differ in their components of the extracellular matrix, the cell wall. The cell wall is an intricate network of proteins and polysaccharides that surrounds the fungal cell and provides structural integrity against internal osmotic pressure. Drugs that inhibit synthases for cell wall polysaccharides weaken this extracellular structure, resulting in lysis of the fungal cell. Whereas inhibitors for beta-glucan synthases have reached the clinic, no inhibitors for alpha-glucan synthases have been developed thus far.

The synthase for cell wall alpha-glucan is a remarkable multidomain protein with two enzyme domains located at opposite sides of the plasma membrane. Our research on the model yeast Schizosaccharomyces pombe is set out to unravel how this complex protein functions at a molecular level. Furthermore, fungal cells express not only enzymes that synthesize structural cell wall polysaccharides but also enzymes that are able to break them down. We showed that S. pombe cells express two distinct alpha-glucanases for the localized hydrolysis of cell wall alpha-glucan. The knowledge gathered from these studies will be applied to the pathogenic fungi Cryptococcus neoformans.