Benjamin J. Gross, Brian C. Kraybill, and Suzanne Walker
Department of Microbiology and Molecular Genetics, HarVard Medical School, 200 Longwood AVenue, Boston,
Massachusetts 02115, and Department of Chemistry and Chemical Biology, HarVard UniVersity
Abstract
Many nuclear and cytosolic proteins are transiently glycosylated
by an enzyme known as O-GlcNAc transferase (OGT), which
transfers N-acetylglucosamine from UDP-GlcNAc to selected serine
and threonine residues. O-GlcNAcylation affects such diverse
cellular processes as transcription, translation, organelle targeting,
and protein-protein interactions,1 and is believed to play a role in
a variety of signaling cascades that mediate glucose homeostasis
and stress responses.2 Specific inhibitors of OGT could be valuable
tools to probe the biological functions of O-GlcNAcylation, but
the inability to obtain significant quantities of enzyme, combined
with the lack of a high-throughput assay, has impeded efforts to
identify such compounds.3 We have developed conditions to express
large quantities of the catalytic domain of active OGT for the first
time, and we report a high-throughput donor displacement assay
for the enzyme along with the discovery of a set of small-molecule
inhibitors. This work lays the foundation for both structural and
functional analysis of the catalytic domain of OGT.
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