Probing Enzymes Late in the Trypanosomal Glycosylphosphatidylinositol Biosynthetic Pathway with Synthetic Glycosylphosphatidylinositol Analogues

Michael D. Urbaniak, Dmitry V. Yashunsky, Arthur Crossman, Andrei V. Nikolaev, Michael A. J. Ferguson (Lead / Corresponding author)

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    22 Citations (Scopus)

    Abstract

    Glycosylphosphatidylinositol (GPI)-anchored proteins are abundant in the protozoan parasite Tryponosoma brucei, the causative agent of African sleeping sickness in humans and the related disease Nagana in cattle, and disruption of GPI biosynthesis is genetically and chemically validated as a drug target. Here, we examine the ability of enzymes of the trypanosomal GPI biosynthetic pathway to recognize and process a series of synthetic dimannosyl-glucos-aminylphosphatidylinositol analogues containing systematic modifications on the mannose residues. The data reveal which portions of the natural substrate are important for recognition, explain why mannosylation occurs prior to inositol acylation in the trypanosomal pathway, and identify the first inhibitor of the third alpha-mannosyltransferase of the GPI biosynthetic pathway.

    Original languageEnglish
    Pages (from-to)625-634
    Number of pages10
    JournalACS Chemical Biology
    Volume3
    Issue number10
    DOIs
    Publication statusPublished - Oct 2008

    Keywords

    • AFRICAN SLEEPING SICKNESS
    • DE-N-ACETYLASE
    • PHOSPHATIDYLINOSITOL MEMBRANE ANCHORS
    • VARIANT SURFACE GLYCOPROTEIN
    • GPI BIOSYNTHESIS
    • INOSITOL-ACYLATION
    • SUBSTRATE-SPECIFICITY
    • TRANSFERRIN RECEPTOR
    • BRUCEI
    • INHIBITION

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