Inhibition of O-GlcNAcase using a potent and cell-permeable inhibitor does not induce insulin resistance in 3T3-L1 adipocytes.
Inhibition of O-GlcNAcase using a potent and cell-permeable inhibitor does not induce insulin resistance in 3T3-L1 adipocytes.
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DOI：
10.1016/j.chembiol.2010.07.006
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发表时间：
2010-09-24
影响因子：
--
通讯作者：
Vocadlo DJ
中科院分区：
文献类型：
--
作者：
Macauley MS;He Y;Gloster TM;Stubbs KA;Davies GJ;Vocadlo DJ
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. ► 6-Ac-Cas is a potent inhibitor (KI = 300 nM) of human O-GlcNAcase ► The structure of an OGA homolog with 6-Ac-Cas reveals the basis for inhibition ► 6-Ac-Cas elevates O-GlcNAc levels in cells in a time- and dose-dependent manner ► 6-Ac-Cas does not cause insulin resistance in cultured 3T3-L1 adipocytes
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DOI：
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影响因子：
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