GlcNAcstatins are nanomolar inhibitors of human O-GlcNAcase inducing cellular hyper-O-GlcNAcylation

• DOI: 10.1042/bj20090110
• Publication Date: 2009-03-17T15:32:00Z
• Authors: Helge C. Dorfmueller; Vladimir S. Borodkin; Marianne Schimpl; Daan M. F. van Aa...
• Keywords: Rational design; SIRT2

O-GlcNAcylation is an essential, dynamic and inducible post-translational glycosylation of cytosolic proteins in metazoa can show interplay with protein phosphorylation. Inhibition OGA (O-GlcNAcase), the enzyme that removes O-GlcNAc from O-GlcNAcylated proteins, a useful strategy to probe role this modification range cellular processes. In present study, we report rational design evaluation GlcNAcstatins, family potent, competitive selective inhibitors human OGA. Kinetic experiments recombinant reveal GlcNAcstatins are most potent reported date, inhibiting sub-nanomolar nanomolar range. Modification GlcNAcstatin N-acetyl group leads up 160-fold selectivity against lysosomal hexosaminidases which employ similar substrate-assisted catalytic mechanism. Mutagenesis studies bacterial OGA, guided by structure complex, provides insight into conserved residues active site. cell-permeant and, at low concentrations, effectively modulate intracellular levels through inhibition cell lines. Thus these compounds tools study biology O-GlcNAc.