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ArtOxiZymes Report Summary

Project ID: 657755
Funded under: H2020-EU.1.3.2.

Periodic Reporting for period 1 - ArtOxiZymes (Artificial Oxidation Enzymes for Highly Selective Waste Free Hydroxylation of Alkanes)

Reporting period: 2015-10-01 to 2017-09-30

Summary of the context and overall objectives of the project

One of the major challenges facing the chemical industries is the sustainable production of chemicals from natural resources. The challenge
includes making sure that chemical processes are as ‘green’ and economical as possible, and that sustainable and abundant resources are used
where possible. One type of reaction that lends itself to sustainable processes is the direct functionalization of C-H to C-X (X = O, N, C) bonds, as
it generates far less chemical waste and leads to tremendous reduction of energy use than methods relying on prefunctionalized materials. The
objective of this project is to achieve the C1-selective hydroxylation of n-alkanes to give n-alcohols e.g. octane to octan-1-ol, using mild reaction
conditions and green oxidants such as oxygen or hydrogen peroxide, which is currently an unsolved problem. Linear alcohols are of interest as
they form some of the major building blocks used in the chemical industries, for example C8-C10 alcohols for the synthesis of plasticisers and
detergents. We will achieve this aim by combining traditional homogenous catalysis and biocatalysis for the development of artificial
metalloenzymes as catalysts, which utilise the molecular recognition concepts of nature to bind substrates selectively in protein pockets. The target
substrate will thus be bound in the correct orientation enabling selective oxidation at the target position, in contrast to traditional chemocatalysts
which give a highly unfavourable product distribution. This will lead to more efficient use of valuable feedstocks and large reductions in chemical
waste production and energy consumption, compared to the traditional methods for forming C1-alcohols, all contributing to a green and
sustainable society.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

A library of artifical metalloenzymes (ArMs) containing N-ligand based cofactors has been prepared. Initial testing in benchmark oxidation reactions was carried out. At this point it became clear that a key objective would be to characterise the ArM in detail to understand the metal binding environment and to evaluate that the desired metal binding was observed (i.e. at the cofactor as opposed to elsewhere in the protein scaffold). Whilst computational modelling was undertaken it quickly became clear that more physical data would be needed to help our understanding. Work at this point turned to understanding the environment in a related ArM - a rhodium phosphine-modified protein. Using a variety of techniques we were able to identify that there is an interaction between one of the amino acids (a methionine) and the metal centre. This work was published in Angewandte Chemie in 2017. Work is now focusing on exploiting our understanding in other reactions, such as oxidations.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

Artificial metalloenzymes is an fast growing field of catalysis research. Our work has introduced a successful example of a phosphine-based catalysts being introduced into a protein scaffold to carry out an industrially relevant transformation – hydroformylation of long chain alkenes to aldehydes. The protein scaffold provided an opportunity to overcome a number of limitations which affect the current commercial catalyst system and we achieved enzyme like rate enhancements. Rational design based on bioinformatics showed that temperature stability could be improved, leading to higher space-time-yields. These promising results indicate that next step needed will searching for similar protein structures from extremophiles which can lead to more robust systems and actual industrial applications. By combining analytical techniques from a range of chemical sub-disciplines we have been able to move towards understanding the active site of our catalysis, and away from mere speculation. This use of many techniques will be important for all practitioners of ArM research in the future as in many cases the characterisation of the metalloenzyme catalyst is lacking in the literature.

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