PARASITE AND MAMMALIAN GPI BIOSYNTHETIC PATHWAYS CAN BE DISTINGUISHEDUSING SYNTHETIC SUBSTRATE-ANALOGS

Glycosylphosphatidylinositol (GPI) structures are attached to many cel l surface glycoproteins in lower and higher eukaryotes. GPI structures are particularly abundant in trypanosomatid parasites where they can be found attached to complex phosphosaccharides, as well as to glycopr oteins, and as mature surface glycolipids. The high density of GPI str uctures at all life-cycle stages of African trypanosomes and Leishmani a suggests that the GPI biosynthetic pathway might be a reasonable tar get for the development of anti-parasite drugs. In this paper we show that synthetic analogues of early GPI intermediates having the 2-hydro xyl group of the D-myo-inositol residue methylated are recognized and mannosylated by the GPI biosynthetic pathways of Trypanosoma brucei an d Leishmania major but not by that of human (HeLa) cells. These findin gs suggest that the discovery and development of specific inhibitors o f parasite GPI biosynthesis are attainable goals. Moreover, they demon strate that inositol acylation is required for mannosylation in the He La cell GPI biosynthetic pathway, whereas it is required far ethanolam ine phosphate addition in the T. brucei GPI biosynthetic pathway.