Completed Diabetes, Hormones & Metabolism Genetics & Molecular Biology

Molecular mechanisms of O-GlcNAc signalling.

Funder Wellcome Charity-funded
Recipient organisation University of Dundee
Funding £1.9M
Period Jun 2009 — Feb 2016

In plain English

AI plain-English summary

Inside human cells, a sugar molecule called O-GlcNAc attaches to thousands of proteins, subtly altering their behaviour in ways that scientists are only beginning to understand. This project tackles a fundamental gap in biology: how cells use sugar-based signals to control protein function. The O-GlcNAc modification is regulated by just two enzymes—OGT and OGA—and it competes with phosphorylation, a better-known process that governs everything from insulin signalling to nerve cell growth. The "Yin-Yang hypothesis" suggests O-GlcNAc acts as a global, glucose-dependent switch that tunes phosphorylation across the cell. But the molecular details remain unknown. The researcher will synthesise chemical inhibitors to block OGT and OGA, solve their three-dimensional structures, and map how O-GlcNAc alters the activity of key proteins in insulin response, neuronal development, and energy balance. They will also investigate whether pathogenic bacteria use similar enzymes to hijack host proteins. This is fundamental science. It will not produce a drug or a diagnostic tomorrow. But understanding how cells read sugar signals could eventually reveal new targets for treating metabolic diseases like diabetes, neurological disorders, or infections where bacteria subvert host cell machinery. Past work on similar post-translational modifications—like phosphorylation—transformed medicine; this could do the same for a less explored layer of cellular control.

View original technical description
Post-translational modification of eukaryotic protein serines/threonines with N-acetylglucosamine (O-GlcNAc) was discovered 20 years ago. Subsequent work has shown that O-GlcNAcylation is regulated by a tranferase (OGT) and a hydrolase (OGA), both single, essential genes, conserved from C. elegans to humans, and that a plethora of proteins in the nucleoplasm are O-GlcNAcylated. Excitingly, there are examples of O-GlcNAcylation having interplay with phosphorylation, including competition for the same serines/threonines, giving rise to the Yin-Yang hypothesis , that proposes O-GlcNAc as a global, glucose dependent, mechanism to control protein phosphorylation. I aim to use a multi-disciplinary approach to uncover the molecular mechanisms governing O-GlcNAcylation and its importance in a number of signal transduction pathways. Capitalising on a significant body or preliminary data, the aims are to: 1) Synthesize/discover OGA/OGT inhibitors and substrate analogues, including glycopeptide s. 2) Determine the structures of human OGA/OGT, including inhibitor/protein substrate complexes and probe mechanism/specificity with mutagenesis and in vitro assays. 3) Understand the effect of O-GlcNAc on phosporylation/activity on key signalling proteins in pathways involve in the insulin response, neuronal development and energy stasis. 4) Investigate whether orthologues of these enzymes in pathogenic bacteria are involved in prokaryotic O-GlcNAc and/or are virulence factors targetting ho st proteins.

View the original record at the funder ↗

Researchers

Daan van Aalten (EPMC Awardee)

Related Research

Grants with similar aims, by meaning.

Structural and Fragment approaches to the modulation of O-GlcNAc in cells
Studies of the O-GlcNAc Modification
Mechanisms of O-GlcNAc signalling .
Investigations Into the Regulation of Plasticity of O-Linked Glycosylation and its Functional Significance
O-Glc-NAc modifications of RNA-binding proteins

Original classification

Senior Research Fellowship Basic Renewal

Plain English summaries and category classifications on this site are generated by AI and may not perfectly reflect the original research.