Schematic of OGT glycosyltransferase activity. Here, OGT catalyzes the O-GlcNAcylation of the globular blue protein.
OGT Overview
OGT is a glycosyltransferase found in the nucleus, cytoplasm, and mitochondria. It transfers the monosaccharide O-GlcNAc to over a thousand proteins, thus occupying a unique biological niche because all other mammalian glycosyltransferases act in the secretory pathway to assemble large oligosaccharides.
ogt conservation
OGT is one of the most conserved human proteins—and the most conserved human glycosyltransferase. While it is essential for cell growth and proliferation, its essential functions are not yet known.
ogt structure
OGT is made up of two main domains—the catalytic domain (light blue) responsible for glycosyltransferase and protease activity, and the tetratricopeptide repeat (TPR) domain (light green) responsible for substrate and adaptor binding. Here, the structure of an inhibitor (red) bound at the active site and a peptide substrate (dark blue) bound through the TPR lumen are shown.
ogt activities
OGT has three distinct activities:
1) It acts as a glycosyltransferase,
2) as a protease,
3) and it has noncatalytic functions.
Composite structure from PDB structures XXXX and XXXX.
OGT is a proposed target for treating cancers and cardiometabolic disorders. Our goals are to understand OGT’s essential functions and to develop inhibitors to disrupt those functions. We are using structure, biochemistry, genetics, and -omics technologies to deconvolute OGT.
To read more about some of our work on OGT, please see the selected publications below.
selected publications
Levine, Z. G.; Potter, S. C.; Joiner, C. M.; Fei, G. Q.; Nabet, B.; Sonnett, M.; Zachara, N. E.; Gray, N. S.; Paulo, J. A.; Walker, S. Mammalian cell proliferation requires noncatalytic functions of O-GlcNAc transferase. Proc. Natl. Acad. Sci. U. S. A. 2021, 118 (4), e2016778118. [PubMed Link] [Publisher Link]
Tan, Z.-W.; Fei, G.; Paulo, J. A.; Bellaousov, S.; Martin, S. E. S.; Duveau, D. Y.; Thomas, C. J.; Gygi, S. P.; Boutz, P. L.; Walker, S. O-GlcNAc regulates gene expression by controlling detained intron splicing. Nucleic Acids Res. 2020, 48 (10), 5656-5669. [PubMed Link] [Publisher Link]
Joiner, C. M.; Levine, Z. G.; Aonbangkhen, C.; Woo, C. M.; Walker, S. Aspartate Residues Far from the Active Site Drive O-GlcNAc Transferase Substrate Selection. J. Am. Chem. Soc. 2019, 141 (33), 12974-12978. [PubMed Link] [Publisher Link]
Martin, S. E. S.; Tan, Z.-W.; Itkonen, H. M.; Duveau, D. Y.; Paulo, J. A.; Janetzko, J.; Boutz, P. L.; Törk, L.; Moss, F. A.; Thomas, C. J.; Gygi, S. P.; Lazarus, M. B.; Walker, S. Structure-Based Evolution of Low Nanomolar O-GlcNAc Transferase Inhibitors. J. Am. Chem. Soc. 2018, 140 (42), 13542-13545. [PubMed Link] [Publisher Link]
Levine, Z. G.; Fan, C.; Melicher, M. S.; Orman, M.; Benjamin, T.; Walker, S. O-GlcNAc Transferase Recognizes Protein Substrates Using an Asparagine Ladder in the Tetratricopeptide Repeat (TPR) Superhelix. J. Am. Chem. Soc. 2018, 140 (10), 3510-3513. [PubMed Link] [Publisher Link]
Janetzko, J.; Trauger, S. A.; Lazarus, M. B.; Walker, S. How the glycosyltransferase OGT catalyzes amide bond cleavage. Nat. Chem. Biol. 2016, 12 (11), 899-901. [PubMed Link] [Publisher Link]
Ortiz-Meoz, R. F.; Jiang, J.; Lazarus, M. B.; Orman, M.; Janetzko, J.; Fan, C.; Duveau, D. Y.; Tan, Z.-W.; Thomas, C. J.; Walker, S. A Small Molecule That Inhibits OGT Activity in Cells. ACS Chem. Biol. 2015, 10 (6), 1392-1397. [PubMed Link] [Publisher Link]
Lazarus, M. B.; Jiang, J.; Kapuria, V.; Bhuiyan, T.; Janetzko, J.; Zandberg, W. F.; Vocadlo, D. J.; Herr, W.; Walker, S. HCF-1 Is Cleaved in the Active Site of O-GlcNAc Transferase. Science 2013, 342 (6163), 1235-1239. [PubMed Link] [Publisher Link]
Lazarus, M. B.; Jiang, J.; Gloster, T. M.; Zandberg, W. F.; Whitworth, G. E.; Vocadlo, D. J.; Walker, S. Structural snapshots of the reaction coordinate for O-GlcNAc transferase. Nat. Chem. Biol. 2012, 8 (12), 966-968. [PubMed Link] [Publisher Link]
Lazarus, M. B.; Nam, Y.; Jiang, J.; Sliz, P.; Walker, S. Structure of human O-GlcNAc transferase and its complex with a peptide substrate. Nature 2011, 469 (7331), 564-567. [PubMed Link] [Publisher Link]