Hijacking a biosynthetic pathway yields a glycosyltransferase inhibitor within cells

Nat Chem Biol. 2011 Mar;7(3):174-81. doi: 10.1038/nchembio.520. Epub 2011 Jan 23.


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 EC(50). 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylglucosaminidase / antagonists & inhibitors*
  • Acetylglucosaminidase / metabolism
  • Biosynthetic Pathways*
  • Cytoplasm / chemistry
  • Cytoplasm / drug effects*
  • Cytoplasm / metabolism
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Protein Processing, Post-Translational / drug effects*


  • Enzyme Inhibitors
  • Acetylglucosaminidase

Associated data

  • PubChem-Substance/103910756
  • PubChem-Substance/103910757
  • PubChem-Substance/103910758
  • PubChem-Substance/103910759
  • PubChem-Substance/103910760
  • PubChem-Substance/103910761
  • PubChem-Substance/103910762
  • PubChem-Substance/103910763
  • PubChem-Substance/103910764
  • PubChem-Substance/103910765
  • PubChem-Substance/103910766
  • PubChem-Substance/103910767
  • PubChem-Substance/103910768
  • PubChem-Substance/103910769
  • PubChem-Substance/103910770
  • PubChem-Substance/103910771
  • PubChem-Substance/103910772
  • PubChem-Substance/103910773
  • PubChem-Substance/103910774
  • PubChem-Substance/103910775
  • PubChem-Substance/103910776
  • PubChem-Substance/103910777
  • PubChem-Substance/103910778
  • PubChem-Substance/103910779
  • PubChem-Substance/103910780
  • PubChem-Substance/103910781
  • PubChem-Substance/103910782
  • PubChem-Substance/103910783
  • PubChem-Substance/103910784