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 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.
journal_name
Nat Chem Bioljournal_title
Nature chemical biologyauthors
Gloster TM,Zandberg WF,Heinonen JE,Shen DL,Deng L,Vocadlo DJdoi
10.1038/nchembio.520subject
Has Abstractpub_date
2011-03-01 00:00:00pages
174-81issue
3eissn
1552-4450issn
1552-4469pii
nchembio.520journal_volume
7pub_type
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