An inhibitor of the human UDP-GlcNAc 4-epimerase identified from a uridine-based library: a strategy to inhibit O-linked glycosylation

Chem Biol. 2002 Jan;9(1):113-29. doi: 10.1016/s1074-5521(02)00093-5.

Abstract

The biological study of O-linked glycosylation is particularly problematic, as chemical tools to control this modification are lacking. An inhibitor of the UDP-GlcNAc 4-epimerase that synthesizes UDP-GalNAc, the donor initiating O-linked glycosylation, would be a powerful reagent for reversibly inhibiting O-linked glycosylation. We synthesized a 1338 member library of uridine analogs directed to the epimerase by virtue of substrate mimicry. Screening of the library identified an inhibitor with a K(i) value of 11 microM. Tests against related enzymes confirmed the compound's specificity for the UDP-GlcNAc 4-epimerase. Inhibitors of a key step of O-linked glycan biosynthesis can be discovered from a directed library screen. Progeny thereof may be powerful tools for controlling O-linked glycosylation in cells.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Carbohydrate Epimerases / antagonists & inhibitors*
  • Carbohydrate Epimerases / metabolism
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacology*
  • Glycosylation
  • Humans
  • Peptide Library
  • Peptides / chemical synthesis
  • Peptides / chemistry
  • Peptides / pharmacology
  • Uridine / metabolism

Substances

  • Enzyme Inhibitors
  • Peptide Library
  • Peptides
  • Carbohydrate Epimerases
  • UDP-N-acetylglucosamine 4-epimerase
  • Uridine