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

TY - JOUR

T1 - Specificity of GlcNAc-Pl de-N-acetylase of GPI biosynthesis and synthesis of parasite-specific suicide substrate inhibitors

AU - Smith, Terry K.

AU - Crossman, Arthur

AU - Borissow, Charles N.

AU - Paterson, Michael J.

AU - Dix, Alex

AU - Brimacombe, John S.

AU - Ferguson, Michael A. J.

PY - 2001/7/2

Y1 - 2001/7/2

N2 - 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.

AB - 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.

U2 - 10.1093/emboj/20.13.3322

DO - 10.1093/emboj/20.13.3322

M3 - Article

SN - 0261-4189

VL - 20

SP - 3322

EP - 3332

JO - EMBO Journal

JF - EMBO Journal

IS - 13

ER -