Article abstract
Nature Chemical Biology 4, 483 - 490 (2008)
Published online: 29 June 2008 | doi:10.1038/nchembio.96
A potent mechanism-inspired O-GlcNAcase inhibitor that blocks phosphorylation of tau in vivo
Scott A Yuzwa1, Matthew S Macauley2, Julia E Heinonen2, Xiaoyang Shan1, Rebecca J Dennis3, Yuan He3, Garrett E Whitworth2, Keith A Stubbs2, Ernest J McEachern2, Gideon J Davies3 & David J Vocadlo1,2
Abstract
Pathological hyperphosphorylation of the microtubule-associated protein tau is characteristic of Alzheimer's disease (AD) and the associated tauopathies. The reciprocal relationship between phosphorylation and O-GlcNAc modification of tau and reductions in O-GlcNAc levels on tau in AD brain offers motivation for the generation of potent and selective inhibitors that can effectively enhance O-GlcNAc in vertebrate brain. We describe the rational design and synthesis of such an inhibitor (thiamet-G, Ki = 21 nM; 1) of human O-GlcNAcase. Thiamet-G decreased phosphorylation of tau in PC-12 cells at pathologically relevant sites including Thr231 and Ser396. Thiamet-G also efficiently reduced phosphorylation of tau at Thr231, Ser396 and Ser422 in both rat cortex and hippocampus, which reveals the rapid and dynamic relationship between O-GlcNAc and phosphorylation of tau in vivo. We anticipate that thiamet-G will find wide use in probing the functional role of O-GlcNAc in vertebrate brain, and it may also offer a route to blocking pathological hyperphosphorylation of tau in AD.
- Department of Molecular Biology and Biochemistry, Simon Fraser University, 8888 University Drive, Burnaby, British Columbia V5A 1S6, Canada.
- Department of Chemistry, Simon Fraser University, 8888 University Drive, Burnaby, British Columbia V5A 1S6, Canada.
- York Structural Biology Laboratory, Department of Chemistry, The University of York, Heslington, York YO10 5YW, UK.
Correspondence to: David J Vocadlo1,2 e-mail: dvocadlo@sfu.ca
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