title: Increasing O-GlcNAc levels: An overview of small-molecule inhibitors of O-GlcNAcase.
abstract: The O-GlcNAc modification is found on many nucleocytoplasmic proteins. The dynamic nature of O-GlcNAc, which in some ways is reminiscent of phosphorylation, has enabled investigators to modulate the stoichiometry of O-GlcNAc on proteins in order to study its function. Although several genetic and pharmacological methods for manipulating O-GlcNAc levels have been described, one of the most direct approaches of increasing global O-GlcNAc levels is by using small-molecule inhibitors of O-GlcNAcase (OGA). As the interest in increasing O-GlcNAc levels has grown, so too has the number of OGA inhibitors. This review provides an overview of the available methods of increasing O-GlcNAc levels, with a special emphasis on inhibition of OGA by small molecules. Known inhibitors of OGA are discussed with particular attention on those most suitable for cell-based biological studies. Several examples in which OGA inhibitors have been used to study the functional role of the O-GlcNAc modification in biological systems are discussed, highlighting the pros and cons of different inhibitors.
authors: Department of Chemistry, Simon Fraser University, Burnaby, British Columbia, Canada.
authors: Matthew S
authors: MS
authors: Macauley
authors: David J
authors: DJ
authors: Vocadlo
mesh_terms: D000117:Acetylglucosamine / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D000118:Acetylglucosaminidase / Q000037:antagonists & inhibitors*; D000818:Animals; D020134:Catalytic Domain; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D017351:N-Acetylglucosaminyltransferases / Q000096:biosynthesis; D010091:Oximes / Q000494:pharmacology; D048448:Phenylcarbamates / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D013311:Streptozocin / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D014537:Uridine Diphosphate N-Acetylglucosamine / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D010091:Oximes; D048448:Phenylcarbamates; D011720:Pyrazoles; D011725:Pyridines; D013844:Thiazoles; C077641:nagstatin; C068836:N-acetylglucosaminono-1,5-lactone O-(phenylcarbamoyl)oxime; D014537:Uridine Diphosphate N-Acetylglucosamine; D013311:Streptozocin; D017351:N-Acetylglucosaminyltransferases; C449880:O-GlcNAc transferase; D000118:Acetylglucosaminidase; C487818:N-acetylglucosamine thiazoline; D000117:Acetylglucosamine