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 language | English |
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Pages (from-to) | 174-181 |
Number of pages | 8 |
Journal | Nature Chemical Biology |
Volume | 7 |
Issue number | 3 |
DOIs | |
Publication status | Published - Mar 2011 |
Keywords
- O-GLCNAC TRANSFERASE
- BETA-N-ACETYLGLUCOSAMINE
- NUCLEOCYTOPLASMIC PROTEINS
- GLYCOSYLATION
- MECHANISM
- ACID
- PHOSPHORYLATION
- GLCNACYLATION
- CATALYSIS
- CLONING