Structural and cellular studies on O-GlcNAc and related glycosylations
Lead Research Organisation:
University of York
Department Name: Chemistry
Abstract
The control of cellular function through the co- and post-translational O-GlcNAc modification is one of the emerging themes of modern cell biology. Of particular note is the link to neurodegenerative diseases, notably the tauopathies, where the modification stabilizes tau and reduced toxic aggregation and Parkinson's disease. The PhD will study the molecular basis of the O-GlcNAc, and related, glycosylations through a combination of X-ray crystallography, inhibitor design and analysis, rational protein engineering and chemical biology. The ultimate goal is to provide a structural and mechanistic description of the human enzyme system and to use this to inform cellular studies probing enzyme inhibition in a therapeutic context.
Publications
Van Rijssel ER
(2017)
Conformational Behaviour of Azasugars Based on Mannuronic Acid.
in Chembiochem : a European journal of chemical biology
Sernee MF
(2019)
A Family of Dual-Activity Glycosyltransferase-Phosphorylases Mediates Mannogen Turnover and Virulence in Leishmania Parasites.
in Cell host & microbe
Rovira C
(2020)
Mannosidase mechanism: at the intersection of conformation and catalysis.
in Current opinion in structural biology
Males A
(2017)
Conformational Analysis of the Mannosidase Inhibitor Kifunensine: A Quantum Mechanical and Structural Approach.
in Chembiochem : a European journal of chemical biology
Males A
(2019)
Distortion of mannoimidazole supports a B2,5 boat transition state for the family GH125 a-1,6-mannosidase from Clostridium perfringens.
in Organic & biomolecular chemistry
Males A
(2019)
Structural studies of a surface-entropy reduction mutant of O-GlcNAcase
in Acta Crystallographica Section D Structural Biology
King DT
(2019)
Molecular mechanisms regulating O-linked N-acetylglucosamine (O-GlcNAc)-processing enzymes.
in Current opinion in chemical biology
González-Cuesta M
(2022)
Bicyclic Picomolar OGA Inhibitors Enable Chemoproteomic Mapping of Its Endogenous Post-translational Modifications.
in Journal of the American Chemical Society
Alonso-Gil S
(2017)
Computational Design of Experiment Unveils the Conformational Reaction Coordinate of GH125 a-Mannosidases.
in Journal of the American Chemical Society
Studentship Projects
| Project Reference | Relationship | Related To | Start | End | Student Name |
|---|---|---|---|---|---|
| BB/M011151/1 | 01/10/2015 | 30/09/2023 | |||
| 1644614 | Studentship | BB/M011151/1 | 01/10/2015 | 30/09/2019 |
| Description | Carbohydrate active enzymes assist the formation and breakdown of saccharides. The enzymes are classified into families according to their reaction pathway. The research conducted in this award showed the importance of designing drugs that bind to enzymes along the reaction pathway. This can lead to tightly bound and highly effective drugs. The enzymes investigated in this project were of high interest as they are involved in protein folding, bacterial colonisation and Alzheimer's disease. Novel inhibitors for these enzymes were identified to understand more about the function of the enzymes. |
| Exploitation Route | Identifying the reaction pathways for carbohydrate enzymes could lead to the design of tight binding drugs. Identifying novel inhibitors could lead to clinical trials and use of these inhibitors as therapeutics. |
| Sectors | Chemicals,Healthcare,Pharmaceuticals and Medical Biotechnology |
| Description | Wild Overseas Scholars Fund |
| Amount | £1,100 (GBP) |
| Funding ID | N0000504 |
| Organisation | University of York |
| Sector | Academic/University |
| Country | United Kingdom |
| Start | 06/2017 |
| End | 08/2017 |
| Description | Compound analysis |
| Organisation | Leiden University |
| Country | Netherlands |
| Sector | Academic/University |
| PI Contribution | Crystal structure proteins in complex with compounds sent from Leiden. |
| Collaborator Contribution | NMR, chemical analysis and synthesis of the compounds. |
| Impact | 10.1002/cbic.201700080 |
| Start Year | 2015 |
| Description | Compounds |
| Organisation | University of Melbourne |
| Country | Australia |
| Sector | Academic/University |
| PI Contribution | Crystal structures of proteins in complex with a synthesised compound (either inhibitor or natural substrate/product). |
| Collaborator Contribution | Synthesis of compounds for crystallisation |
| Impact | 10.1021/jacs.6b11247. 10.1002/cbic.201700166 |
| Start Year | 2015 |
| Description | Computational collaboration |
| Organisation | University of Barcelona |
| Country | Spain |
| Sector | Academic/University |
| PI Contribution | Obtained protein structures with experimental crystallography of compounds of GH125 and GH47 proteins. Resulted in 2 papers. |
| Collaborator Contribution | Computational QM/MM experiments of the proteins GH125 and GH47 in complex with ligands. |
| Impact | 10.1021/jacs.6b11247. 10.1002/cbic.201700166 |
| Start Year | 2015 |