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CARBAZYMES Report Summary

Project ID: 635595
Funded under: H2020-EU.2.1.4.

Periodic Reporting for period 1 - CARBAZYMES (Sustainable industrial processes based on a C-C bond-forming enzyme platform)

Reporting period: 2015-04-01 to 2016-09-30

Summary of the context and overall objectives of the project

Project Context and Objectives

Large-scale industrial production of chemicals often takes place with reduced efficiency and produces large quantities of toxic waste. Improved biocatalysts for carbon-carbon bond construction such as those to be developed within the CarbaZymes project will lead to novel safer and more efficient industrial processes, for the benefit of industry, consumers and the environment.
Products of industrial organic synthesis such as pharmaceuticals and bulk chemicals contribute significantly to the quality of life and the economic development of modern societies. However, industrial chemical processes carried out through “classic” chemistry and catalysis often involve the use of hazardous substances and considerable amounts of energy. In contrast, enzymes are natural catalysts that speed up the manufacture and modification of molecules under mild reaction conditions and with exquisite selectivity, leading to increased product yields. Thus, the application of enzymes (“biocatalysis”) to catalyze industrial reactions offers an important potential to improve chemical manufacturing processes by reducing the use of corrosive chemicals, organic solvents, toxic metals and energy, in compliance with the concept and principles of Green Chemistry.
Carbon-carbon bond forming reactions are key processes in industrial organic synthesis to construct advanced molecules of high value, but remain insufficiently explored due to the lack of robust enzymes that cover a sufficiently wide range of reactions. To bridge the gap between laboratory experiments and industrial large-scale production, the scientists behind CarbaZymes address these challenges by developing a broad toolbox of carbon-carbon bond forming enzymes and by improving their properties so that these enzymes can be applied in new sustainable industrial processes with reduced environmental footprints. The CarbaZymes project will pursue the biocatalytic synthesis of several valuable compounds, spanning a range of four chiral fine chemicals and three bulk chemicals, corresponding to market needs detected by the industrial partners in the consortium.

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

Work performed and main results

The overall objective of the CarbaZymes project was to construct a platform of robust enzymes for diverse types of carboligation reactions, and to demonstrate their potential for large-scale synthesis under industrial constraints. With the project having completed the first 18-months period of its work program, the consortium has successfully established advanced tools to identify and develop a broad panel of improved enzymes for carbon-carbon bond formation in a supra-disciplinary manner. The toolbox of methodologies includes the construction of bioinformatics tools, tests for high-throughput reaction analysis, protein structure modeling, as well as fast protocols for mutagenesis and stabilization of enzymes. Microreactor technology has been set up for bioprocess characterization and advanced reaction engineering. A bioinformatics information system was set up to facilitate in-depth data mining for the several target enzyme superfamilies to aid in the discovery and development of novel biocatalysts. Structural models were built to support a deeper understanding of structure-function relationships within the known natural variety. Tools could be advanced that allow increasing the stability of a given enzyme at higher temperatures.
Using these advanced tools, several superfamily libraries of novel enzymes were produced on a wider scale, which were subsequently tested for their performance characteristics in various reactions within the scope of the project against a collection of known enzymes. Several key enzymes could be identified among the first and higher generations of novel catalysts that show significantly better properties and that are promising for further development as well as for assembly into efficient catalytic reaction cascades. Libraries of mutant enzymes were constructed in a search for catalysts having improved properties for the target reactions by in-vitro-evolution and high-throughput screening. Several engineered enzymes were identified to catalyze highly selective conversions, which give access to new chiral building blocks that are potentially valuable for industrial production but originally were not foreseen to be accessible with previously known biocatalysts. A novel total synthesis protocol was achieved for the integrated synthesis of an amino acid precursor with high volumetric productivity. Necessary information to implement carboligation processes at larger scale was obtained for modeling of the reaction systems, which will allow a more detailed analysis for the development of scalable syntheses of target compounds. Activities for a pilot-plant demonstration are scheduled in the next period to verify the economical feasibility of selected processes at a larger scale. Patent applications have already been filed, or are under way, to secure intellectual property rights for the consortium.
The CarbaZymes project has a strong emphasis on disseminating this growing knowledge to the wider public. A comprehensive program was devised and started for public dissemination of results, including original scientific publications, workshops and practical training courses, participation in key biotechnology conferences and the creation of an explanatory video (under production) addressing both experts and the public. Moreover, promotion of white biotechnology via networking events and contacts to the general public through internet presence, newsletter and social media channels is ongoing.

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)

Potential impact

The CarbaZymes outcomes are expected to make a notable social and economic impact, by responding timely and efficiently to pressurizing market needs from an increasing and aging population, by addressing markets worth billions and creating new intellectual property. CarbaZymes aims to promote innovation in the field of carbon-carbon bond formation at large scale, by developing natural enzyme-catalyzed routes to important specialty and bulk chemical precursors. The range of novel and improved biocatalysts generated from this research will also provide opportunities for the synthesis of many further valuable products, thus having a profound impact on reducing emissions, energy consumption and toxic waste. By developing new intellectual property as well as advancing biotechnology know-how — a Key Enabling Technology for Europe — this project aims to strengthen the global competitiveness of the European chemical, biotechnological and pharmaceutical industries.

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