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M002151200v1
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Papers In Press, published online ahead of print May 31, 2000
J. Biol. Chem, 10.1074/jbc.M002151200
Submitted on March 13, 2000
Revised on May 17, 2000
Accepted on May 30, 2000

Developmental stage-specific biosynthesis of glycosylphosphatidylinositol anchors in intraerythrocytic {italics plasmodium falciparum} and its inhibition in a novel manner by mannosamine

Ramachandra S. Naik, Eugene E. Davidson, and D. Channe Gowda

Department of Biochemistry and Molecular Biology, Georgetown Universiy Medical Center, Washington, DC 20007

Corresponding Author: gowda{at}bc.georgetown.edu

Summary Glycosylphosphatidylinositols (GPIs) are the major glycoconjugates in intraerythrocytic stage {italics Plasmodium falciparum}. Several functional proteins including merozoite surface protein 1 are anchored to the cell surface by GPI modification, and GPIs are vital to the parasite. Here, we studied the developmental stage-specific biosynthesis of GPIs by intraerythrocytic {italics P. falciparum}. The parasite synthesizes GPIs exclusively during the maturation of early trophozoites to late trophozoites but not during the development of rings to early trophozoites, or late trophozoites to schizonts and merozoites. Mannosamine, an inhibitor of GPI biosynthesis, inhibits the growth of the parasite specifically at the trophozoite stage, preventing further development to schizonts and causing death. Mannosamine has no effect on the development of either rings to early trophozoites or late trophozoites to schizonts and merozoites. The analysis of GPIs and proteins synthesized by the parasite in the presence of mannosamine demonstrates that the effect is due to 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-PI intermediate, which is distinctively different from the pattern seen in other organisms. In other systems, mannosamine inhibits GPI biosynthesis by interfering with either the transfer of a mannose residue to the Manalpha 1-6Manalpha 1-4GlcN-PI intermediate or the formation of ManN-Man-GlcN-PI, an aberrant GPI intermediate, which cannot be a substrate for further addition of mannose. Thus, the parasite GPI biosynthetic pathway could be a specific target for anti-malarial drug development.


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