Proteomics and PUGNAcity will overcome questioning of insulin resistance induction by nonselective inhibition of O-GlcNAcase


Correspondence: Dr. Tony Lefebvre, CNRS-UMR 8576, Unit of Structural and Functional Glycobiology, IFR 147, University of Lille 1, 59655, Villeneuve d'Ascq, France


Fax: +33-3-20-43-65-55


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.