Biosynthesis of glycosylphosphatidylinositols of Plasmodium falciparum in a cell-free incubation system: inositol acylation is needed for mannosylation of glycosylphosphatidylinositols

The structures of glycosylphosphatidylinositols (GPIs) in Plasmodium have b een described [Gerold, Schuppert and Schwarz (1994) J. Biol. Chem. 269, 259 7-2606]. A detailed understanding of GPI synthesis in Plasmodium is a prere quisite for identifying differences present in biosynthetic pathways of par asites and host cells. A comparison of the biosynthetic pathway of GPIs has revealed differences between mammalian cells and parasitic protozoans. A c ell-free incubation system prepared from asexual erythrocytic stages of Pla smodium falciparum, the causative agent of malaria in humans, is capable of synthesizing the same spectrum of GPIs as that found in metabolically labe lled parasites. The formation of mannosylated GPIs in the cell-free system is shown to be inhibited by GTP and, unexpectedly, micromolar concentration s of GDP-Man. Lower concentrations of GDP-Man affect the spectrum of GPIs s ynthesized. The inositol ring of GPIs of P. falciparum is modified by an ac yl group. The preferred donor of this fatty acid at the inositol ring is my ristoyl-Coa. Inositol acylation has to precede the mannosylation of GPIs be cause, in the absence of acyl-CoA or CoA, mannosylated GPIs were not detect ed. Inositol myristoylation is a unique feature of plasmodial GPIs and thus might provide a potential target for drug therapy.