Hijacking a biosynthetic pathway yields a glycosyltransferase inhibitor within cells

Tracey M. Gloster, Wesley F. Zandberg, Julia E. Heinonen, David L. Shen, Lehua Deng, David J. Vocadlo

Research output: Contribution to journalArticlepeer-review

198 Citations (Scopus)

Abstract

Glycosyltransferases are ubiquitous enzymes that catalyze the assembly of glycoconjugates throughout all kingdoms of nature. A long-standing problem is the rational design of probes that can be used to manipulate glycosyltransferase activity in cells and tissues. Here we describe the rational design and synthesis of a nucleotide sugar analog that inhibits, with high potency both in vitro and in cells, the human glycosyltransferase responsible for the reversible post-translational modification of nucleocytoplasmic proteins with O-linked N-acetylglucosamine residues (O-GlcNAc). We show that the enzymes of the hexosamine biosynthetic pathway can transform, both in vitro and in cells, a synthetic carbohydrate precursor into the nucleotide sugar analog. Treatment of cells with the precursor lowers O-GlcNAc in a targeted manner with a single-digit micromolar EC50. This approach to inhibition of glycosyltransferases should be applicable to other members of this superfamily of enzymes and enable their manipulation in a biological setting.

Original languageEnglish
Pages (from-to)174-181
Number of pages8
JournalNature Chemical Biology
Volume7
Issue number3
DOIs
Publication statusPublished - Mar 2011

Keywords

  • O-GLCNAC TRANSFERASE
  • BETA-N-ACETYLGLUCOSAMINE
  • NUCLEOCYTOPLASMIC PROTEINS
  • GLYCOSYLATION
  • MECHANISM
  • ACID
  • PHOSPHORYLATION
  • GLCNACYLATION
  • CATALYSIS
  • CLONING

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