Biosynthetic Pathway of GPI-anchored Cell Wall Mannoproteins in Yeast as a Potential Target for Anti-fungal and Anti-cancer Drugs

Abstract

Glycosylphosphatidyl-inositol (GPI) -anchored mannoproteins are one of the major cell wall components of eukaryotic microorganisms, including yeast and fungi. Some GPI-anchored proteins are localized at the plasma membrane, but others are processed at the plasma membrane and are covalently linked to beta-1, 6-glucan of the cell wall through the GPI portion. The genes and enzymes responsible for their biosynthesis and cell wall assembly are potential targets of anti-fungal reagents. We identified GWT1 as a new anti-fungal drug candidate target and elucidated its function as being involved in the acylation of the inositol ring. We also found a new function of GPI7 , which is involved in transfer of ethanolamine phosphate to Man2 of GPI. Our results indicate that the localization of GPI-anchored endoglucanase Egt2p is displaced from the septal region to the cell cortex at the restrictive temperature in gpi7 mutant cells, suggesting that GPI7 is involved in the separation of mother and daughter cells and its defective phenotype is a good marker to select a new inhibitor of Gpi7 function. We have also reported that PER1 is involved in lipid remodeling of GPI-anchored proteins, indicating that Per1p has a GPI-phospholipase A2 activity to eliminate the unsaturated fatty acyl chain at the sn-2 position of PI moiety. We further found that human PERLD1 , which is now known as an oncogene, is a functional homologue of yeast PER1 , indicating that this is a potential target for new anti-cancer drugs.