O-GlcNAc transferase (OGT) is an essential mammalian enzyme that catalyzes a unique post-translational modification, O-GlcNAcylation. O-GlcNAcylation has been shown to modulate insulin signaling, gluconeogenesis, and other pathways connected to glucose metabolism. Hyper-O-GlcNAcylation leads to widespread transcriptional changes and has been linked to diabetic complications, cancer, and other pathologies. Therefore, it has been suggested that OGT could be a therapeutic target. A better understanding of the structure and function of OGT is critical for dissecting its biological roles, and small molecule inhibitors are widely sought by the scientific community. The goals of this proposal are i) to supply the structural basis for rational experiments to dissect the biochemical and cellular functions of OGT, ii) to provide validated small molecule inhibitors for use as cellular probes of OGT function, and iii) to develop a proteome-wide substrate profiling approach to identify OGT features required for substrate selection.

Public Health Relevance

O-GlcNAc transferase (OGT) is an essential mammalian enzyme that catalyzes a unique post-translational modification, O-GlcNAcylation. This modification mediates critical cellular processes involved in nutrient signaling, stress responses, and cell division. Aberrant O-GlcNAcylation has been linked to many diseases, and the work proposed here will lead to the development of small molecule inhibitors to probe OGT's biological roles and potential as a therapeutic target.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM094263-02
Application #
8415976
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Marino, Pamela
Project Start
2012-02-01
Project End
2016-01-31
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
2
Fiscal Year
2013
Total Cost
$498,749
Indirect Cost
$202,326
Name
Harvard University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
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Lazarus, Michael B; Jiang, Jiaoyang; Kapuria, Vaibhav et al. (2013) HCF-1 is cleaved in the active site of O-GlcNAc transferase. Science 342:1235-9