Substrate and product analogues as human O-GlcNAc transferase inhibitors

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,...

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Bibliographic Details
Published in:	Amino acids 2011-03, Vol.40 (3), p.781-792
Main Authors:	Dorfmueller, Helge C, Borodkin, Vladimir S, Blair, David E, Pathak, Shalini, Navratilova, Iva, van Aalten, Daan M. F
Format:	Article
Language:	eng
Subjects:	Acetylglucosamine - metabolism Analytical Chemistry Biochemical Engineering Biochemistry Biomedical and Life Sciences crystal structure Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology Glycosylation Humans Inhibitor Kinetics Life Sciences N-Acetylglucosaminyltransferases - antagonists & inhibitors N-Acetylglucosaminyltransferases - chemistry N-Acetylglucosaminyltransferases - genetics N-Acetylglucosaminyltransferases - metabolism Neurobiology O-GlcNAc Original Original Article post-translational modification Protein Binding Proteins - metabolism Proteomics Signalling Substrate Specificity
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Summary:	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.
ISSN:	0939-4451 1438-2199