Inositol acylation of glycosylphosphatidylinositols in the pathogenic fungus Cryptococcus neoformans and the model yeast Saccharomyces cerevisiae

Cryptococcus neoformans, an opportunistic fungus responsible for life-threa tening infection in immunocompromised patients, is able to synthesize glyco sylphosphatidylinositol (GPI) structures. Radiolabelling experiments in vit ro with the use of a cryptococcal cell-free system showed that the pathway begins as in other eukaryotes, with the addition of N-acetylglucosamine to phosphatidylinositol, followed by deacetylation of the sugar residue. The t hird step, acylation of the inositol ring, seemed to involve a fatty acid o ther than palmitate, in contrast with previous findings in Saccharomyces ce revisiae and mammalian GPI pathways. A systematic study of inositol acylati on in C. neoformans and S. cerevisiae showed that both organisms used a var iety of fatty acids in this step; these were transferred directly from acyl -CoA to inositol without modification. However, the specificity of fatty ac id utilization was quite distinct in the two fungi, with the pathogen being substantially more restrictive. In mammalian cells fatty acids added exoge nously as acyl-CoAs are not transferred directly to inositol. These results suggest significant differences in the GPI biosynthetic pathway between ma mmalian and C. neoformans cells that could represent targets for anti-crypt ococcal therapy.