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Content archived on 2024-05-29

Mechanism and lnhibition of pantothenate synthase

Objective

Pantothenate is vitamin B5, an essential dietary vitamin for humans and animals. The biosyntheticpathway leading to pantothenate has been elucidated, and the enzymes and their correspondinggenes isolated from E. coli. Since pantothenate is made by microorg anisms, plants and fungi, theenzymes which form pantothenate are potentially excellent targets for the design of antimicrobial 01herbicida! agents. This project centers on the enzyme pantothenate synthase, which catalyses the finalstep in the formation of pantothenate. Pantothenate synthase is readily available throughoverexpression of the cloned gene. The recently determined crystal structure of this enzyme will beused as a guide for both parts of this project:(i) detailed studies of the mechanism of actio nSite-directed mutagenesis will be used to probe the mechanistic role of key residues identified fromthe crystal structur, and to form stable enzyme-substrate complexes for structural studies. Thesubstrate specificity of pantothenate synthase will be explo red and attempts made to alter thesubstrate specificity by mutagenesis.(ii) design of enzyme inhibitors.Novel strategies will be used for rational inhibitor design, including Click chemistry andenzyme-templated dynamic combinatorial chemistry (DCC). Studie s using Click chemistry will initiallyuse a range of azides and alkynes based on the pantoate and adenosine, reacting via templating inthe presence of the enzyme, and so favouring products which bind the enzyme most tightly. Enzyme-templated DCC will invol ve the reversible reactions of pools of molecular fragments using excessenzyme to template the formation of products which bind tightly to the enzyme and so are potentialinhibitors. Fragments for both Click and DCC studies will be chosen using state-of-the -art techniquesincluding in silico molecular docking using GOLD, small molecule-protein binding by 1H NMR.

Fields of science (EuroSciVoc)

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Topic(s)

Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.

Call for proposal

Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.

FP6-2002-MOBILITY-7
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Funding Scheme

Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.

IIF - Marie Curie actions-Incoming International Fellowships

Coordinator

THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE
EU contribution
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Address
The Old Schools, Trinity Lane
CAMBRIDGE
United Kingdom

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Total cost

The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.

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