Specificity of GlcNAc-Pl de-N-acetylase of GPI biosynthesis and synthesis of parasite-specific suicide substrate inhibitors

Terry K. Smith, Arthur Crossman, Charles N. Borissow, Michael J. Paterson, Alex Dix, John S. Brimacombe, Michael A. J. Ferguson

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    The substrate specificities of Trypanosoma brucei and human (HeLa) GlcNAc-PI de-N-acetylases were determined using 24 substrate analogues. The results show the following. (i) The de-N-acetylases show little specificity for the lipid moiety of GlcNAc-PI, (ii) The 3 ' -OH group of the GlcNAc residue is essential for substrate recognition whereas the 6 ' -OH group is dispensable and the 4 ' -OH, while not required for recognition, cannot be epimerized or substituted, (iii) The parasite enzyme can act on analogues containing beta GlcNAc or aromatic N-acyl groups, whereas the human enzyme cannot, (iv) Three GlcNR-PI analogues are de-N-acetylase inhibitors, one of which is a suicide inhibitor, (v) The suicide inhibitor most likely forms a carbamate or thiocarbamate ester to an active site hydroxy-amino acid or Cys or residue such that inhibition is reversed by certain nucleophiles, These and previous results were used to design two potent (IC50 = 8 nM) parasite-specific suicide substrate inhibitors. These are potential lead compounds for the development of anti-protozoan parasite drugs.

    Original languageEnglish
    Pages (from-to)3322-3332
    Number of pages11
    JournalEMBO Journal
    Issue number13
    Publication statusPublished - 2 Jul 2001

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