Metabolic Inhibitors of O‐GlcNAc Transferase That Act In Vivo Implicate Decreased O‐GlcNAc Levels in Leptin‐Mediated Nutrient Sensing
| Autor: | Liu, Tai‐Wei, Zandberg, Wesley F., Gloster, Tracey M., Deng, Lehua, Murray, Kelsey D., Shan, Xiaoyang, Vocadlo, David J. |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
Glycoproteins | Very Important Paper
Leptin Glycosylation Dose-Response Relationship Drug Communication Electrophoresis Capillary Enzyme-Linked Immunosorbent Assay N-Acetylglucosaminyltransferases Communications Acetylglucosamine Substrate Specificity carbohydrates (lipids) Mice inhibitors nucleotide sugars Adipocytes Animals Enzyme Inhibitors Phosphorylation Muscle Skeletal thiosugars glycoproteins |
| Zdroj: | Angewandte Chemie (International Ed. in English) |
| ISSN: | 1521-3773 1433-7851 |
| Popis: | O‐Linked glycosylation of serine and threonine residues of nucleocytoplasmic proteins with N‐acetylglucosamine (O‐GlcNAc) residues is catalyzed by O‐GlcNAc transferase (OGT). O‐GlcNAc is conserved within mammals and is implicated in a wide range of physiological processes. Herein, we describe metabolic precursor inhibitors of OGT suitable for use both in cells and in vivo in mice. These 5‐thiosugar analogues of N‐acetylglucosamine are assimilated through a convergent metabolic pathway, most likely involving N‐acetylglucosamine‐6‐phosphate de‐N‐acetylase (NAGA), to generate a common OGT inhibitor within cells. We show that of these inhibitors, 2‐deoxy‐2‐N‐hexanamide‐5‐thio‐d‐glucopyranoside (5SGlcNHex) acts in vivo to induce dose‐ and time‐dependent decreases in O‐GlcNAc levels in various tissues. Decreased O‐GlcNAc correlates, both in vitro within adipocytes and in vivo within mice, with lower levels of the transcription factor Sp1 and the satiety‐inducing hormone leptin, thus revealing a link between decreased O‐GlcNAc levels and nutrient sensing in peripheral tissues of mammals. |
| Databáze: | OpenAIRE |
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