Multidisciplinary approaches to characterise deacylating enzymes for therapeutic intervention

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The cells in our body contain thousands of different proteins that are essential for the correct structure and functionof our tissues and organs. Protein function is tightly controlled to ensure that the unique and diverse pathwaysthat they regulate are correctly coordinated, for example, through the addition of certainchemical groups - a process called Post-Translational Modification (PTM). One such PTM is 'S-acylation' in which chemical groups called fatty-acids are reversibly attached to specific sites on proteins. We propose an in-depth study of S-acylation as this form of PTM is linked to diseases such as cancer and diabetes, and brain disorders such as schizophrenia, Huntington's disease and Alzheimer's disease.A group of proteins that remove added fatty acids from proteins - called "APT" enzymes - are critical to this S-acylationprocess and underpin normal cellular processes. Cellular APT enzymes belong to a much larger enzyme familyand the total number of APTs is more diverse than previously thought, with several novel APTs having been identified inrecent years. One such important breakthrough in this poorly-understood area of research was my recent discovery of aprotein called 'ABHD16A' as an entirely new APT enzyme. ABHD16A is associated with pain and inflammation and one ofmy current research projects is exploring its potential as a drug target to treat these chronic diseases.This fellowship aims to build on my proven expertise in APT discovery science and in the wider S-acylation field to revealcellular APTs that regulate dynamic S-acylation pathways and identify molecules that inhibit their activity. Thesediscoveries are essential to expedite our understanding of the role of S-acylation in cellular pathways linked to humandiseases and to enable us to explore the potential of APTs to be targeted in new therapeutic interventions.To address these aims, I have put in place the support of a network of collaborators who are international experts inchemical biology, chemical proteomics and molecular modelling and I will use a comprehensive suite of recently-developedcutting-edge techniques that I am experienced in. In collaboration with organic chemists at the University of Strathclyde ledby Prof Nick Tomkinson, I will utilise chemical-biology tools that I have recently developed to accurately measure changesin the level of protein S-acylation following alterations in the level of APT expression in cells. The effects of manipulatingthe expression of APT enzymes will be measured quantitatively at the Proteomics Research Technology Platform, University of Warwick, with Dr Andrew Bottrill andcolleagues who are experts in chemical proteomics, using the most advanced and sensitive mass spectrometry processesavailable. Experts in computational chemistry at Coventry University, led by Prof Chris Reynolds, will use bioinformatics, comparative modelling and molecular dynamic simulations to generate high quality structures for the purpose of understanding function and for the development of compounds that modulate the activity of APT enzymes.Ultimately, this research programme will elucidate how APT enzymes coordinate essential S-acylation processes, pinpointing the mechanisms that are faulty in specific human diseases and identifying new therapeutic targets for thediscovery of novel drugs to treat a range of diseases that threaten global human health.