The School of Molecular and Cellular Biology at the University of Illinois at Urbana-Champaign

Fungal cell walls are dynamic three-dimensional complexes of polysaccharides and glycoproteins that confer cell integrity and dictate cell shape, yet which also permit cell expansion and cell division. Because the wall is essential for cell viability and because surface glycoproteins are important virulence determinants in fungal pathogens, inhibition of cell wall biogenesis should be an excellent strategy for combating fungal infections. Our goals are to define the pathways for biosynthesis of yeast cell wall components and to explore the structure and function of the enzymes involved.

A major focus is on glycosylphosphatidylinositol (GPI) membrane anchors of protein. GPIs have a core structure of protein-CO-NH-CH₂-CH₂-PO₄-6-mannose-α1,2-mannose-α1,6-mannose-α1,4-glucosamine-α1,6-inositol-phospholipid, which becomes decorated with phosphoethanolamine and mannose side-branches. GPIs are built up stepwise by enzymes in the membrane of the rough endoplasmic reticulum, then attached to the COOH terminus of selected glycoproteins. GPI-modified proteins are then transported to the cell surface where they may remain anchored in the external face of the plasma membrane or become cross-linked to the cell wall upon formation of a covalent link between the GPI glycan and cell wall ps. We are using genetics, bioinformatics, molecular biology, and biochemistry to study how GPIs are assembled in Saccharomyces cerevisiae and the human pathogenic fungus Candida albicans, and to clone the genes involved. Our work with gpi mutants showed that GPIs are essential for viability and for normal cell wall morphogenesis in both S. cerevisiae and C. albicans. Current goals are to carry out structure-function studies of GPI biosynthetic enzymes, and to apply chemical biological approaches to the analysis of GPI assembly. We are particularly interested in steps in GPI assembly that have no essential counterpart in mammals, and which are therefore potential targets for new antifungal drugs. Such agents are sorely needed to combat the fungal infections that afflict immunocompromised patients.

Further interests are the structure, function, and regulation of the complex membrane-bound enzymes that synthesize cell wall polysaccharides such as chitin.