Inhibition of O-GlcNAcase by PUGNAc is dependent upon the oxime stereochemistry.
The potent O-GlcNAcase inhibitor PUGNAc was synthesized and two isomers based on the E and Z stereochemistry of the oxime moiety were separated, defined, and tested for activity. Several lines of evidence were examined in an effort to define the correct stereochemical assignments of each form of PUGNAc. The ability of the Z stereoisomer to undergo the Beckmann rearrangement was ultimately the most definitive proof. It was determined via both in vitro and intact cell experiments that the Z form of PUGNAc was vastly more potent an inhibitor of O-GlcNAcase than the E form.
Perreira
Melissa
M
Chemical Biology Core Facility, National Institute of Diabetes and Digestive and Kidney Disorders, National Institutes of Health, Bethesda, MD 20892, USA.
Kim
Eun Ju
EJ
Thomas
Craig J
CJ
Hanover
John A
JA
D000117:Acetylglucosamine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000118:Acetylglucosaminidase / Q000037:antagonists & inhibitors*; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006367:HeLa Cells; D051548:Histone Acetyltransferases / Q000037:antagonists & inhibitors*; D006801:Humans; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors*; D010091:Oximes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D048448:Phenylcarbamates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D013237:Stereoisomerism; D001619:beta-N-Acetylhexosaminidases
D004791:Enzyme Inhibitors; D009097:Multienzyme Complexes; D010091:Oximes; D048448:Phenylcarbamates; D011994:Recombinant Proteins; C068836:N-acetylglucosaminono-1,5-lactone O-(phenylcarbamoyl)oxime; D051548:Histone Acetyltransferases; C110628:hexosaminidase C; D000118:Acetylglucosaminidase; D001619:beta-N-Acetylhexosaminidases; D000117:Acetylglucosamine