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Content archived on 2024-06-18

Identification of a general biosynthetic pathway of 3-acyltetronates and further investigation of the biosynthetic pathway of the ionophoric polyethers tetronasin and tetronomycin

Objective

A main aim of the research project is the elucidation of a general biosynthetic pathway of 3-acyltetronates. For this purpose, enzymes, which were identified in the gene clusters of the phosphatase inhibitor RK-682 and the quasi-enantiomeric ionophoric polyethers tetronasin and tetronomycin to be potentially responsible for tetronate formation will be heterologously expressed in E.coli. The purified enzymes will be applied for the development of in vitro assays with synthetically prepared surrogates. Besides the identification of a distinct biosynthetic pathway of 3-acyltetronates, the use of structurally diverse synthetic precursors will allow to draw conclusions about the substrate specifity of these enzymes. After expression of further enzymes from the tetronasin and the tetronomycin gene cluster, these enzymes will also be incubated with suggestive synthetic precursor analogues. Understanding the mechanism of 3-acyltetronate formation in RK-682 and the ionophoric polyethers tetronasin and tetronomycin will help to elucidate the mechanisms, which leads to the formation of other tetronate containing natural products like kijanimicin and abyssomycin. The information gained from these experiments will afford the application of the tetronate forming enzymes in the frame of combinatorial biosynthesis. It will permit the incorporation of tetronate forming enzymes into artificial biosynthetic assembly lines to generate novel and more potent agents by directed biosynthesis. Furthermore, all tailoring enzymes, e.g. these arranging for the highly stereoselective ring closures, will find an application in biocatalytic transformations once they were identified. Finally, elucidation of the whole post-PKS steps will help to understand the oddity of nature that created two complex, nearly perfect enantiomers, tetronasin and tetronomycin, which have more or less the same function and mode of action.

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Topic(s)

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Call for proposal

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FP7-PEOPLE-IEF-2008
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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.

MC-IEF - Intra-European Fellowships (IEF)

Coordinator

THE CHANCELLOR MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE
EU contribution
€ 171 300,62
Address
TRINITY LANE THE OLD SCHOOLS
CB2 1TN CAMBRIDGE
United Kingdom

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Region
East of England East Anglia Cambridgeshire CC
Activity type
Higher or Secondary Education Establishments
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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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