Inhibition of microbial β-N-acetylhexosaminidases by 4-deoxy- and galacto-analogues of NAG-thiazoline

Bioorg Med Chem Lett. 2014 Nov 15;24(22):5321-3. doi: 10.1016/j.bmcl.2014.09.066. Epub 2014 Oct 2.

Abstract

NAG-thiazoline is a well-established competitive inhibitor of two physiologically relevant glycosidase families-β-N-acetylhexosaminidases (GH20) and β-N-acetylglucosaminidases (GH84). Based on the different substrate flexibilities of these enzyme groups, we designed and synthesized the 4-deoxy derivative of NAG-thiazoline aiming at the selective inhibition of GH20 β-N-acetylhexosaminidases. One GH84 and two GH20 microbial glycosidases were employed as model enzymes for the inhibition assays. Surprisingly, the new compound 4-deoxy-thiazoline exhibited no activity inhibition with either of the enzyme families of interest. Unlike with the substrates, the 4-hydroxyl group of the inhibitor's sugar ring seems to be crucial for binding the inhibitor to the active sites of these enzymes.

Keywords: Enzyme inhibition; NAG-thiazoline; O-GlcNAcase; β-N-Acetylhexosaminidase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylglucosamine / analogs & derivatives*
  • Acetylglucosamine / chemical synthesis
  • Acetylglucosamine / chemistry
  • Acetylglucosamine / metabolism
  • Bacterial Proteins / antagonists & inhibitors*
  • Bacterial Proteins / metabolism
  • Bacteroides / enzymology
  • Fungal Proteins / antagonists & inhibitors*
  • Fungal Proteins / metabolism
  • Fungi / enzymology
  • Kinetics
  • Protein Binding
  • Streptomyces / enzymology
  • Substrate Specificity
  • Thiazoles / chemical synthesis
  • Thiazoles / chemistry*
  • Thiazoles / metabolism
  • beta-N-Acetylhexosaminidases / antagonists & inhibitors*
  • beta-N-Acetylhexosaminidases / metabolism

Substances

  • Bacterial Proteins
  • Fungal Proteins
  • Thiazoles
  • beta-N-Acetylhexosaminidases
  • N-acetylglucosamine thiazoline
  • Acetylglucosamine