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.
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.
|Sherman, David J; Lazarus, Michael B; Murphy, Lea et al. (2014) Decoupling catalytic activity from biological function of the ATPase that powers lipopolysaccharide transport. Proc Natl Acad Sci U S A 111:4982-7|
|Janetzko, John; Walker, Suzanne (2014) The making of a sweet modification: structure and function of O-GlcNAc transferase. J Biol Chem 289:34424-32|
|Ortiz-Meoz, Rodrigo F; Merbl, Yifat; Kirschner, Marc W et al. (2014) Microarray discovery of new OGT substrates: the medulloblastoma oncogene OTX2 is O-GlcNAcylated. J Am Chem Soc 136:4845-8|
|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|