Glycosylphosphatidylinositol (GPI) structures are attached to many cell 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 glycoproteins, and as mature surface glycolipids. The high density of GPI structures at all life-cycle stages of African trypanosomes and Leishmania suggests that the GPI biosynthetic pathway might be a reasonable target for the development of anti-parasite drugs. In this paper we show that synthetic analogues of early GPI intermediates having the 2-hydroxyl group of the D-myo-inositol residue methylated are recognized and mannosylated by the GPI biosynthetic pathways of Trypanosoma brucei and Leishmania major but not by that of human (HeLa) cells. These findings suggest that the discovery and development of specific inhibitors of parasite GPI biosynthesis are attainable goals. Moreover, they demonstrate that inositol acylation is required for mannosylation in the HeLa cell GPI biosynthetic pathway, whereas it is required for ethanolamine phosphate addition in the T.brucei GPI biosynthetic pathway.
African sleeping sickness is a debilitating and often fatal disease caused by tsetse fly transmitted African trypanosomes. These extracellular protozoan parasites survive in the human bloodstream by virtue of a dense cell surface coat made of variant surface glycoprotein. The parasites have a repertoire of several hundred immunologically distinct variant surface glycoproteins and they evade the host immune response by antigenic variation. All variant surface glycoproteins are anchored to the plasma membrane via glycosylphosphatidylinositol membrane anchors and compounds that inhibit the assembly or transfer of these anchors could have trypanocidal potential. This article compares glycosylphosphatidylinositol biosynthesis in African trypanosomes and mammalian cells and identifies several steps that could be targets for the development of parasite-specific therapeutic agents.
Unlike other α‐mannopyranoside‐2‐sulphonates, the 2‐O‐trifluoromethylsulfonyl (trifluoromethanesulfonate) derivative, (II), underwent an SN2 displacement with an azide ion to give methyl (2′R,3′R)‐2‐azido‐2,6‐dideoxy‐3,4‐O‐(2′,3′‐dimethoxybutane‐2′,3′‐diyl)‐α‐l‐glucopyranoside, C13H23N3O6, (IV), in preference to the E2 reaction.
In the title compound, C20H30O9S, (III), both six‐membered rings adopt chair conformations, placing H3 and the 2‐sulfon yloxy group in the antiperiplanar arrangement required for an E2 reaction. However, unlike other α‐mannopyranoside‐2‐sulfonates, the 2‐O‐trifluoromethylsulfonyl (trifluoromethanesulfonate) derivative, (II), underwent an SN2 displacement with an azide ion to give methyl (2′R,3′R)‐2‐azido‐2,6‐dideoxy‐3,4‐O‐(2′,3′‐dimethoxybutane‐2′,3′‐diyl)‐α‐l‐glucopyranoside, (IV), in preference to the E2 reaction.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.