title: Proteomics and PUGNAcity will overcome questioning of insulin resistance induction by nonselective inhibition of O-GlcNAcase.
abstract: PTMs are the ultimate elements that perfect the existence and the activity of proteins. Owing to PTM, not less than 500 millions biological activities arise from approximately 20 000 protein-coding genes in human. Hundreds of PTM were characterized in living beings among which is a large variety of glycosylations. Many compounds have been developed to tentatively block each kind of glycosylation so as to study their biological functions but due to their complexity, many off-target effects were reported. Insulin resistance exemplifies this problem. Several independent groups described that inhibiting the removal of O-GlcNAc moieties using O-(2-acetamido-2-deoxy-d-glucopyranosylidene)amino-N-phenylcarbamate (PUGNAc), a nonselective inhibitor of the nuclear and cytoplasmic O-GlcNAcase, induced insulin resistance both in vivo and ex vivo. The development of potent and highly selective O-GlcNAcase inhibitors called into question that elevated O-GlcNAcylation levels are responsible for insulin resistance; these compounds not recapitulating the insulin-desensitizing effect of PUGNAc. To tackle this intriguing problem, a South Korean group recently combined ATP-affinity chromatography and gel-assisted digestion to identify proteins, differentially expressed upon treatment of 3T3-L1 adipocytes with PUGNAc, involved in protein turnover and insulin signaling.
authors: CNRS-UMR 8576, Unit of Structural and Functional Glycobiology, IFR 147, University of Lille 1, Villeneuve d'Ascq, France.
authors: Vanessa
authors: V
authors: Dehennaut
authors: Tony
authors: T
authors: Lefebvre
mesh_terms: D041721:3T3-L1 Cells; D000117:Acetylglucosamine / Q000031:analogs & derivatives* / Q000378:metabolism; D000818:Animals; D002846:Chromatography, Affinity; D006031:Glycosylation; D056945:Hep G2 Cells; D006801:Humans; D007333:Insulin Resistance; D051379:Mice; D010091:Oximes / Q000378:metabolism*; D048448:Phenylcarbamates / Q000378:metabolism*; D040901:Proteomics / Q000379:methods*; D001619:beta-N-Acetylhexosaminidases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D010091:Oximes; D048448:Phenylcarbamates; C068836:N-acetylglucosaminono-1,5-lactone O-(phenylcarbamoyl)oxime; C110628:hexosaminidase C; D001619:beta-N-Acetylhexosaminidases; D000117:Acetylglucosamine
keywords: Biomedicine; Hexosaminidases inhibitors; Insulin signaling; O-GlcNAcylation; PUGNAc; Ubiquitination