Developmental stage-specific biosynthesis of glycosylphosphatidylinositol anchors in intraerythrocytic Plasmodium falciparum and its inhibition in a novel manner by mannosamine

Glycosylphosphatidylinositols (GPIs) are the major glycoconjugates in intra erythrocytic stage Plasmodium falciparum. Several functional proteins inclu ding merozoite surface protein 1 are anchored to the cell surface by GPI mo dification, and GPIs are vital to the parasite. Here, we studied the develo pmental stage-specific biosynthesis of GPIs by intraerythrocytic P. falcipa rum. Tie parasite synthesizes GPIs exclusively during the maturation of ear ly trophozoites to late trophozoites but not during the development of ring s to early trophozoites or late trophozoites to schizonts and merozoites, M annosamine, an inhibitor of GPI biosynthesis, inhibits the growth of the pa rasite specifically at the trophozoite stage, preventing further developmen t to schizonts and causing death. Mannosamine has no effect on the developm ent of either rings to early trophozoites or late trophozoites to schizonts and merozoites. The analysis of GPIs and proteins synthesized by the paras ite in the presence of mannosamine demonstrates that the effect is because of the inhibition of GPI biosynthesis, The data also show that mannosamine inhibits GPI biosynthesis by interfering with the addition of mannose to an inositol-acylated GlcN-phosphatidylinositol (PI) intermediate, which is di stinctively different from the pattern seen in other organisms. In other sy stems, mannosamine inhibits GPI biosynthesis by interfering with either the transfer of a mannose residue to the Man alpha 1-6Man alpha 1-4GlcN-PI int ermediate or the formation of ManN-Man-GlcN-PI, an aberrant GPI intermediat e, which cannot be a substrate for further addition of mannose. Thus, the p arasite GPI biosynthetic pathway could be a specific target for antimalaria l drug development.