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Details of Grant 

EPSRC Reference: EP/N03001X/1
Title: Fluorovinyl thioethers as stereoelectronic mimetics of acyl co-enzyme-A enol/ates
Principal Investigator: O'Hagan, Professor D
Other Investigators:
Researcher Co-Investigators:
Project Partners:
Department: Chemistry
Organisation: University of St Andrews
Scheme: Standard Research
Starts: 01 April 2016 Ends: 31 May 2019 Value (£): 400,859
EPSRC Research Topic Classifications:
Biological & Medicinal Chem. Catalysis & enzymology
EPSRC Industrial Sector Classifications:
Pharmaceuticals and Biotechnology Chemicals
Related Grants:
Panel History:
Panel DatePanel NameOutcome
18 Feb 2016 EPSRC Physical Sciences Chemistry - February 2016 Announced
Summary on Grant Application Form
Enzymes are biological catalysts that carry out the reactions of metabolism. They are found in all living forms such as higher mammals, plants and bacteria. If an enzyme reaction in a plant or a bacterium can be selectively inhibited, then there are prospects of developing agrochemical agents such as herbicides if we can inhibit plant enzymes, or antibiotics if we inhibit bacterial enzymes.

Enzyme inhibition is an established strategy in agrochemicals and pharmaceuticals research.

One way of designing enzyme inhibitors is to mimic, at the molecular level, an unstable intermediate in the chemical process, because the enzyme is good at binding to unstable intermediates, and processing them efficiently. That is how they carry out their catalysis. The ingenuity for the researcher comes in trying to design a suitable stable mimic of an unstable intermediate. This is a challenge, but if it can be achieved, then a strategy for enzyme inhibition opens up.

This proposal aims to mimic enol or/and enolate intermediates, that are thought to be transient on the surface of enzymes, when they are carrying out their catralytic function. An enolate has an oxygen atom attached to a double bond. This is very unstable as it can rearrange to a more stable carbonyl form. The enolate however is stabilised by interactions with the enzyme surface, as a means of its proper functioning.

In this proposal, the oxygen attached to the enolate double bond will be replaced by a fluorine. This is a vinylfluoride. This is stable, and we have shown by computer modelling that it has approximately the same electronic profile as an enolate. This is a new idea, and the proposal will aim to explore this at the enzyme level.

Two of the three enzymes selected are important to the agrochemical industry, enzymes that have been the focus of inhibition to prepare herbicides. Thes enzymes are acetyl CoA carboxylase (ACC), trans enoyl Co-A-reductase. The enzymes utilise co-enzyme-A esters. Co-enzyme-A is a relatively complex biomolecule, and it challenging to prepare derivatives of it in the way that is envisaged. However in preliminary work we have developed a chemical method to prepare the required fluorovinyl thioether, and a biochemical (enzyme) method to eleborate the synthesised motif into a fully formed co-enzyme-A derivative. The excitement now is to prepare full co-enzyme-A derivatives of the fluorovinyl thioether motif, and assess their ability to bind to and also inhibit appropriate enzymes.

One aspect of the proposal is to assess how important the fluorine atom is in mimicking the oxygen atom. Therefore analogues will be prepared with fluorine, and then without fluorine, replacing it for a hydrogen. The working hypothesis anticipates that there will be a significant fluorine effect. There are several methods for assessing if the co-enzyme-A derivatives will bind to the enzymes, and also for assessing their relative affinities. This involves enzymes assays, and assessing if the motif is a good inhibitor (strong binder). This can also be assessed by calorimetry (ITC), where good binding leads to an exotherm, and heat is evolved. The lab has good instrumentation for detailed enzyme assay and calorimetry analysis.

We also plan to co-crystallise our elaborate co-enzyme-A derivatives with the enzymes. These are mimetics of reactive intermediates (enolates) and they should bind tightly to the enzyme surface. X-ray analysis will enable us to look very closley as to how this mimetic binds into the enzyme pocket.

At the end of the programme we will be able demonstrate how to introduce and manipulate this new fluorine containing motif, and its potential in enzyme inhibition. The focus here is orientated towards agrochemicals reserach, however the principles that emerge will be equally applicable to pharmaceuticals research, and rational approachedsto enzyme inhibition more generally.
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Organisation Website: http://www.st-and.ac.uk