Hijacking a biosynthetic pathway yields a glycosyltransferase inhibitor within cells
Open Access
- 23 January 2011
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Chemical Biology
- Vol. 7 (3), 174-181
- https://doi.org/10.1038/nchembio.520
Abstract
Feeding of modified carbohydrates has previously led to metabolic incorporation of these compounds into cellular glycans. Now the strategic use of a thiol analog that can be converted into an activated sugar but not incorporated into glycans provides a potent intracellular glycosyltransferase inhibitor. 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.Keywords
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