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Unlocking Fe(II)/αKG-dioxygenase enzymes as sustainable biocatalysts for the synthesis of isonitriles

Objective

Isonitriles are valuable organic molecules endowed with unique reactivity features, which find wide applications in a variety of chemical fields, from material sciences to chemical biology, organic, and medicinal chemistry. Current methods to prepare isonitriles suffer from major drawbacks in terms of safety and sustainability, as they rely on the use of large amounts of highly toxic chemicals (e.g. COCl2, POCl3, TMSCN), which make their synthesis hazardous and wasteful, especially for industrial-scale production. Based on the established ability of biocatalytic strategies to enable milder, greener, and more selective chemical processes, the aim of this project is to investigate, characterise, and engineer the protein ScoE from Streptomyces coeruleorubidus and related isonitrile-forming enzymes from the Fe(II)/KG-dioxygenase superfamily with the final goal to turn them into a new class of biocatalysts for the sustainable production of isonitrile compounds. The project will first characterise wild-type ScoE in order to optimise the biotransformation parameters and to evaluate the in vitro catalytic performances of the enzyme and its natural substrate scope (specificity and selectivity). In parallel, representative isonitrile-forming Fe(II)/KG-dioxygenases with potential for different activity and selectivity will be selected from assorted environmental niches and assessed for their substrate flexibility and their ability to biocatalyse the synthesis of isonitrile derivatives in vitro. Such investigations will provide experimental data to drive the identification of best candidates for biocatalyst development. Mutagenesis studies driven by in-silico design will be performed to generate improved Fe(II)/KG-dioxygenase variants (with broader substrate scope) to be exploited as biocatalysts. The hit enzymes will be produced on larger scale and biocatalytic methods for the preparative synthesis of isonitriles will be developed.

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Keywords

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Programme(s)

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Topic(s)

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Funding Scheme

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HORIZON-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European Fellowships

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Call for proposal

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(opens in new window) HORIZON-MSCA-2024-PF-01

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Coordinator

UNIVERSITY COLLEGE LONDON
Net EU contribution

Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.

€ 260 347,92
Address
GOWER STREET
WC1E 6BT LONDON
United Kingdom

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Region
London Inner London — West Camden and City of London
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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