| Inhibition of O-GlcNAcase using a potent and cell-permeable inhibitor does not induce insulin resistance in 3T3-L1 adipocytes. | |
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MedLine Citation:
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PMID: 20851343 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Matthew S Macauley; Yuan He; Tracey M Gloster; Keith A Stubbs; Gideon J Davies; David J Vocadlo |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Chemistry & biology Volume: 17 ISSN: 1879-1301 ISO Abbreviation: Chem. Biol. Publication Date: 2010 Sep |
Date Detail:
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Created Date: 2010-09-20 Completed Date: 2011-01-18 Revised Date: 2011-10-27 |
Medline Journal Info:
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Nlm Unique ID: 9500160 Medline TA: Chem Biol Country: United States |
Other Details:
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Languages: eng Pagination: 937-48 Citation Subset: IM |
Copyright Information:
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Copyright © 2010 Elsevier Ltd. All rights reserved. |
Affiliation:
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Department of Chemistry, Simon Fraser University, Burnaby, BC, Canada. |
| Data Bank Information | |
Bank Name/Acc. No.:
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PDB/2XJ7 |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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3T3-L1 Cells Acetylglucosamine / analogs & derivatives, pharmacology Adipocytes / drug effects*, enzymology, metabolism Animals Binding Sites Catalytic Domain Crystallography, X-Ray Deoxyglucose / metabolism Enzyme Inhibitors / chemistry*, pharmacology Humans Indolizines / chemistry*, pharmacology Insulin / pharmacology* Insulin Receptor Substrate Proteins / metabolism Insulin Resistance Mice Oximes / pharmacology Phenylcarbamates / pharmacology Phosphorylation Proto-Oncogene Proteins c-akt / metabolism beta-N-Acetylhexosaminidases / antagonists & inhibitors*, metabolism |
| Grant Support | |
ID/Acronym/Agency:
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082572//Wellcome Trust; //Canadian Institutes of Health Research |
| Chemical | |
Reg. No./Substance:
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0/6-acetamido-6-deoxycastanospermine; 0/Enzyme Inhibitors; 0/Indolizines; 0/Insulin Receptor Substrate Proteins; 0/Irs1 protein, mouse; 0/Oximes; 0/Phenylcarbamates; 11061-68-0/Insulin; 132489-69-1/N-acetylglucosaminono-1,5-lactone O-(phenylcarbamoyl)oxime; 154-17-6/Deoxyglucose; 7512-17-6/Acetylglucosamine; EC 2.7.11.1/Proto-Oncogene Proteins c-akt; EC 3.2.1.50/hexosaminidase C; EC 3.2.1.52/beta-N-Acetylhexosaminidases |
| Comments/Corrections | |
Erratum In:
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Chem Biol. 2010 Oct 29;17(10):1161 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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