An inhibitor of the human UDP-GlcNAc 4-epimerase identified from a uridine-based library: a strategy to inhibit O-linked glycosylation.
The biological study of O-linked glycosylation is particularly problematic, as chemical tools to control this modification are lacking. An inhibitor of the UDP-GlcNAc 4-epimerase that synthesizes UDP-GalNAc, the donor initiating O-linked glycosylation, would be a powerful reagent for reversibly inhibiting O-linked glycosylation. We synthesized a 1338 member library of uridine analogs directed to the epimerase by virtue of substrate mimicry. Screening of the library identified an inhibitor with a K(i) value of 11 microM. Tests against related enzymes confirmed the compound's specificity for the UDP-GlcNAc 4-epimerase. Inhibitors of a key step of O-linked glycan biosynthesis can be discovered from a directed library screen. Progeny thereof may be powerful tools for controlling O-linked glycosylation in cells.
Winans
Katharine A
KA
Center for New Directions in Organic Synthesis, Department of Chemistry, University of California, Berkeley 94720, USA.
Bertozzi
Carolyn R
CR
D002238:Carbohydrate Epimerases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D006031:Glycosylation; D006801:Humans; D019151:Peptide Library; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D014529:Uridine / Q000378:metabolism
D004791:Enzyme Inhibitors; D019151:Peptide Library; D010455:Peptides; D002238:Carbohydrate Epimerases; C023223:UDP-N-acetylglucosamine 4-epimerase; D014529:Uridine