# Defining OGT's Essential Functions to Guide Therapeutic Approaches

> **NIH NIH R01** · HARVARD MEDICAL SCHOOL · 2021 · $445,542

## Abstract

PROJECT SUMMARY
O-GlcNAc transferase (OGT), an essential human protein, attaches N-acetylglucosamine (GlcNAc) to Ser/Thr
residues of proteins in the nucleus and cytoplasm. Dysregulated OGT expression and activity have been linked
to insulin resistance, diabetic complications, and cancer, making OGT a possible drug target. Developing
approaches to exploit OGT as a target requires understanding its physiological roles and the mechanisms by
which it achieves them. Studies to probe OGT's physiological roles have relied heavily on knockdown (KD) or
conditional knockout (KO) experiments and the resulting phenotypes have been attributed to loss of O-GlcNAc.
However, OGT has a second catalytic activity and also binds cellular proteins that it does not glycosylate; some
phenotypes attributed to O-GlcNAc loss may therefore be due to loss of other activities. Previously, the
importance of OGT's catalytic and noncatalytic functions could not be assessed because methods to replace
endogenous OGT with variants did not exist. We have now established methods to replace OGT and will analyze
cells containing specifically altered copies to deconvolute OGT's physiological roles. Growth phenotypes,
quantitative proteomics, and biochemistry will be used to address several questions. Is OGT's noncatalytic
scaffolding activity a major driver of physiology and what pathways are linked to it? What is the shortest OGT
construct that still supports cell survival and what proteins does it glycosylate and bind? How do OGT's
substrates and binding partners interact with the TPR domain and are there opportunities to target specific
regions of this domain? We will also use a small molecule inhibitor we recently developed in a chemogenomics
screen to identify genetic vulnerabilities to loss of O-GlcNAc. In addition to advancing scientific knowledge about
one of the most fundamentally important proteins in mammalian biology, the work in this proposal will provide
the foundation to guide approaches to exploit OGT as a therapeutic target.

## Key facts

- **NIH application ID:** 10119696
- **Project number:** 2R01GM094263-09A1
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** Suzanne Walker
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $445,542
- **Award type:** 2
- **Project period:** 2012-02-01 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10119696

## Citation

> US National Institutes of Health, RePORTER application 10119696, Defining OGT's Essential Functions to Guide Therapeutic Approaches (2R01GM094263-09A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10119696. Licensed CC0.

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