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Ac-GlcNAc-5S (also known as 5S-GlcNAc or peracetylated 5-thio-GlcNAc) is a cell-permeable small molecule inhibitor of O-GlcNAc transferase (OGT). Chemically, it is a thio-sugar analog of N-acetylglucosamine (GlcNAc) where the pyranose ring oxygen is substituted with sulfur. Upon entering the cell, it is deacetylated and converted into UDP-5S-GlcNAc, which acts as a potent competitive inhibitor of OGT. In the context of oncology research, particularly glioblastoma, Ac-GlcNAc-5S has been shown to disrupt acetate metabolism by preventing the O-GlcNAcylation-dependent stabilization of ACSS2, thereby reducing tumor growth and lipid synthesis. It is primarily utilized as a chemical biology tool to investigate the role of O-linked β-N-acetylglucosamine (O-GlcNAc) post-translational modifications in various disease states, including cancer and neurodegeneration.
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