Selective inhibitors of the glycosylphosphatidylinositol biosynthetic pathway of Trypanosoma brucei

Terry K. Smith, Deepak K. Sharma, Arthur Crossman, John S. Brimacombe, Michael A. J. Ferguson

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    59 Citations (Scopus)


    Synthetic analogues of D-GlcN alpha 1-6D-myo-inositol-1-HPO4-3(sn-1,2-diacylglycerol) (GlcN-PI), with the 2-position of the inositol residue substituted with an O-octyl ether [D-GlcN alpha 1-6D-(2-O-octyl)myo-inositol-1-HPO4-3-sn-1,2-dipalmitoylglycerol; GlcN-(2-O-octyl) PI] or O-hexadecyl ether [D-GlcN alpha 1-6D-(2-O-hexadecyl)myo-inositol-1-HPO4-3-sn-1,2-dipalmitoylglycerol; GlcN-(2-O-hexadecyl)PI], were tested as substrates or inhibitors of glycosylphosphatidylinositol (GPI) biosynthetic pathways using cell-free systems of the protozoan parasite Trypanosoma brucei (the causative agent of human African sleeping sickness) and human HeLa cells. Neither these compounds nor their N-acetyl derivatives are substrates or inhibitors of GPI biosynthetic enzymes in the HeLa cell-free system but are potent inhibitors of GPI biosynthesis in the T.brucei cell-free system. GlcN-(2-O-hexadecyl)PI was shown to inhibit the first alpha-mannosyltransferase of the trypanosomal GPI pathway. The N-acetylated derivative GlcNAc-(2-O-octyl)PI is a substrate for the trypanosomal GlcNAc-PI de-N-acetylase and this compound, like GlcN-(2-O-octyl)PI, is processed predominantly to Man(2)GlcN-(2-O-octyl)PI by the T.brucei cell-free system. Both GlcN-(2-O-octyl)PI and GlcNAc(2-O-octyl)PI also inhibit inositol acylation of Man(1-3)GlcN-PI and, consequently, the addition of the ethanolamine phosphate bridge in the T.brucei cell-free system. The data establish these substrate analogues as the first generation of in vitro parasite GPI pathway-specific inhibitors.

    Original languageEnglish
    Pages (from-to)5922-5930
    Number of pages9
    JournalEMBO Journal
    Issue number21
    Publication statusPublished - 1 Nov 1999


    • Glycosylphosphatidylinositol (GPI)
    • HeLa
    • Inositol acyltransferase
    • Mannosyltransferase
    • Trypanosoma


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