Further probing of the substrate specificities and inhibition of enzymes involved at an early stage of glycosylphosphatidylinositol (GPI) biosynthesis

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

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    18 Citations (Scopus)

    Abstract

    1-D-6-O-(2-Amino-2-deoxy-alpha-D-glucopyranosyl)-1-O-hexadecyl-myo-inositol (14), 1-D-6-O-(2-amino-2-deoxy-alpha-D-glucopyranosyl)-myo-inositol 1-(octadecyl phosphate) (18), 1-D-6-O-(2-amino-2-deoxy-alpha-D-glucopyranosyl)-myo-inositol 1-(1,2-di-O-hexadecanoyl-sn- glycerol 3-phosphate) (24). 1-D-6-O-(2-amino-2-deoxy-alpha-D-mannopyranosyl)-myo-inositol 1-(1,2-di-O-hexadecanoyl-sn- glycerol 3-phosphate) (30) and the corresponding 2-amino-2-deoxy-alpha-D-galactopyranosyl analogue 36 have been prepared and tested in cell-free assays as substrate analogues/inhibitors of alpha-(1-->4)-D-mannosyltransferases that are active early on in the glycosylphosphatidylinositol (GPI) biosynthetic pathways of Trypanosoma brucei and HeLa (human) cells. The corresponding N-acetyl derivatives of these compounds were similarly tested as candidate substrate analogues/inhibitors of the N-deacetylases present in both systems, Following on from an early study, 1-L-6-O-(2-amino-2-deoxy-alpha-D-glucopyranosyl)-2-O-methyl-myo-inositol 1-(1,2-di-O-hexadecanoyl-sn-glycerol 3-phosphate) (44) was prepared and tested as an inhibitor of the trypanosomal alpha-(1-->4)-D-mannosyltransferase. A brief summary of the biological evaluation of the various analogues is provided. (C) 2002 Elsevier Science Ltd. All rights reserved.

    Original languageEnglish
    Pages (from-to)2049-2059
    Number of pages11
    JournalCarbohydrate Research
    Volume337
    Issue number21-23
    DOIs
    Publication statusPublished - 19 Nov 2002

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