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Inhibition of O-GlcNAcase Using a Potent and Cell-Permeable Inhibitor Does Not Induce Insulin Resistance in 3T3-L1 Adipocytes

DOI: 10.1016/j.chembiol.2010.07.006 DOI Help
PMID: 20851343 PMID Help

Authors: Matthew S. Macauley (Simon Fraser University) , Yuan He (University of York) , Tracey M. Gloster (Simon Fraser University) , Keith A. Stubbs (Simon Fraser University) , Gideon J. Davies (University of York) , David J. Vocadlo (Simon Fraser University)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Chemistry & Biology , VOL 17 (9) , PAGES 937 - 948

State: Published (Approved)
Published: September 2010

Open Access Open Access

Abstract: To probe increased O-GlcNAc levels as an independent mechanism governing insulin resistance in 3T3-L1 adipocytes, a new class of O-GlcNAcase (OGA) inhibitor was studied. 6-Acetamido-6-deoxy-castanospermine (6-Ac-Cas) is a potent inhibitor of OGA. The structure of 6-Ac-Cas bound in the active site of an OGA homolog reveals structural features contributing to its potency. Treatment of 3T3-L1 adipocytes with 6-Ac-Cas increases O-GlcNAc levels in a dose-dependent manner. These increases in O-GlcNAc levels do not induce insulin resistance functionally, measured using a 2-deoxyglucose (2-DOG) uptake assay, or at the molecular level, determined by evaluating levels of phosphorylated IRS-1 and Akt. These results, and others described, provide a structural blueprint for improved inhibitors and collectively suggest that increased O-GlcNAc levels, brought about by inhibition of OGA, does not by itself cause insulin resistance in 3T3-L1 adipocytes.

Journal Keywords: Acetylglucosamine; Adipocytes; Animals; Binding; Catalytic; Crystallography; X-Ray; Deoxyglucose; Enzyme; Humans; Indolizines; Insulin; Insulin; Insulin; Mice; Oximes; Phenylcarbamates; Phosphorylation; Proto-Oncogene; beta-N-Acetylhexosaminidases

Subject Areas: Biology and Bio-materials


Instruments: I04-Macromolecular Crystallography

Added On: 03/11/2015 15:32

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