Postgraduate research opportunities A reactive fragment approach to dissect the zDHHC enzymes

Post-translational modifications (PTMs) define an exciting and active area of new medicines discovery research.  This project will be concerned with the delivery of chemical tools to establish the factors involved in determining the acyl chain selectivity observed by the zDHHC family of enzymes which are responsible for S-acylation, a key PTM.  Based upon a new reactive fragment screening platform we will deliver workflows to validate targets within this emerging area of discovery research.

This 48-month project will involve the design, synthesis, isolation, purification and characterisation of small molecules.  Working as part of a team of synthetic chemists and chemical biologists you will be responsible for the delivery of small molecules to interrogate mechanistic biological hypotheses

The project will also involve a 3-month industrial placement at GlaxoSmithKline, Stevenage working within their chemical biology team.

Over 20% of the proteome undergoes reversible post-translational acylation catalysed by the zDHHC family of enzymes.  This dynamic process affects protein trafficking, location and function and disruption has been associated with many disease states.  Protein acylation is a tightly regulated network of transformations whose orchestration is critical to multiple critical pathways that are essential for cellular function.  Despite their potential as therapeutic targets, there is a distinct lack of chemical tools available to understand and dissect the biological processes associated with these enzymes.  This project is concerned with the delivery of a suite of novel tool molecules to define the function and selectivity associated with this intriguing family of enzymes.  This includes establishing rules governing selectivity in acylation and identifying the protein substrates for each enzyme.

It is envisaged this study will provide two key contributions to the field of palmitoylation.  First, the ability to identify substrate proteins for each zDHHC enzyme in a cellular environment that will enable a fundamental understanding of the involvement of these enzymes in complex signalling pathways.  Second, it will define which cysteine residue of a protein substrate is acylated and identify the structure of the fatty acid that is incorporated, providing an accessible method to decipher the palmitoylome.  These tool molecules will provide the platform to investigate treatments for several diseases of unmet clinical need including Schizophrenia, Huntington disease and pancreatic ductal carcinoma.

References

A direct-to-biology high-throughput chemistry approach to reactive fragment screening. Chem. Sci. 2021, 12, 12098–12106.

One-Step Synthesis of Photoaffinity Probes for Live-Cell MS-Based Proteomics. Chem. Eur. J. 2021, 27, 17880–17888.

PhotoAffinity Bits: A Photoaffinity-Based Fragment Screening Platform for Efficient Identification of Protein Ligands. Angew. Chem. Int. Ed. 2020, 59, 21096–21105.

A Photoaffinity Displacement Assay and Probes to Study the Cyclin-Dependent Kinase Family. Angew. Chem. Int. Ed. 2019, 58, 17322–17327.

Development of a novel high-throughput screen for the identification of new inhibitors of protein S-acylation. J. Biol. Chem. 2022, 298, 102469.

Further information

This project is supported by GSK and will provide the opportunity to spend three months in their laboratories in Stevenage.