Discovery of O-GlcNAc transferase inhibitors.
O-GlcNAcylation of serine and threonine residues is a dynamic and essential post-translational modification involved in signaling pathways in eukaryotes. Studies of O-GlcNAcylation would be aided by small-molecule inhibitors of O-GlcNAc transferase (OGT), the sole enzyme know to mediate this modification, but discovery of such molecules has been hampered by poor expression of cloned OGT and lack of suitable high-throughput screens. This Communication describes the development an expression system to access large amounts of the catalytic domain of OGT and the implementation of a fluorescence-based substrate analogue displacement assay that has led to the discovery of a set of OGT inhibitors. This work lays the foundation for both structural and functional analysis of the catalytic domain of OGT.
Gross
Benjamin J
BJ
Department of Microbiology and Molecular Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
Kraybill
Brian C
BC
Walker
Suzanne
S
D002384:Catalysis; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D004926:Escherichia coli / Q000201:enzymology; D006801:Humans; D015394:Molecular Structure; D017351:N-Acetylglucosaminyltransferases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D017351:N-Acetylglucosaminyltransferases; C449880:O-GlcNAc transferase