title: Substrate and product analogues as human O-GlcNAc transferase inhibitors.
abstract: Protein glycosylation on serine/threonine residues with N-acetylglucosamine (O-GlcNAc) is a dynamic, inducible and abundant post-translational modification. It is thought to regulate many cellular processes and there are examples of interplay between O-GlcNAc and protein phosphorylation. In metazoa, a single, highly conserved and essential gene encodes the O-GlcNAc transferase (OGT) that transfers GlcNAc onto substrate proteins using UDP-GlcNAc as the sugar donor. Specific inhibitors of human OGT would be useful tools to probe the role of this post-translational modification in regulating processes in the living cell. Here, we describe the synthesis of novel UDP-GlcNAc/UDP analogues and evaluate their inhibitory properties and structural binding modes in vitro alongside alloxan, a previously reported weak OGT inhibitor. While the novel analogues are not active on living cells, they inhibit the enzyme in the micromolar range and together with the structural data provide useful templates for further optimisation.
authors.affiliation: Division of Molecular Microbiology, College of Life Sciences, University of Dundee, Dundee, Scotland, UK.
authors.forename: Helge C
authors.initials: HC
authors.lastname: Dorfmueller
authors.forename: Vladimir S
authors.initials: VS
authors.lastname: Borodkin
authors.forename: David E
authors.initials: DE
authors.lastname: Blair
authors.forename: Shalini
authors.initials: S
authors.lastname: Pathak
authors.forename: Iva
authors.initials: I
authors.lastname: Navratilova
authors.forename: Daan M F
authors.initials: DM
authors.lastname: van Aalten
mesh_terms: D000117:Acetylglucosamine / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006031:Glycosylation; D006801:Humans; D007700:Kinetics; D017351:N-Acetylglucosaminyltransferases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism; D013379:Substrate Specificity
chemical_list: D004791:Enzyme Inhibitors; D011506:Proteins; D017351:N-Acetylglucosaminyltransferases; C449880:O-GlcNAc transferase; D000117:Acetylglucosamine