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Designer enzymes featuring unnatural amino acids as catalytic residue

Project description

Designer enzymes could make the 'unnatural' the natural choice for greener chemistry

Enzymes are nature's catalysts, speeding up the rate of a reaction without being consumed by it, and thus they can be used again and again. Most enzymes are proteins, sequences of amino acids that form functional (or 'meaningful') compounds, in the same way that a sequence of letters forms words and sentences. Small sequences of amino acids in the enzyme form the binding and catalytic sites, essentially holding the reactant(s) captive so that the reaction can be catalysed. The EU-funded DENZUAC project is out to introduce 'unnatural' amino acids into naturally occurring proteins to unlock a wealth of catalytic reactions currently inaccessible with natural 'green' chemistry. The designer enzymes could help make biocatalysis significantly more attractive as a route to sustainable chemical reactions for a variety of applications of importance to society in fields ranging from energy and medicine to nanotechnology.


Biocatalysis is a key component of the transition towards a more sustainable and “greener” chemistry. Surprisingly, natural enzymes use only a relatively small section of “reaction space”, that is, only limited number of reaction classes. This in marked contrast to the vast reaction space available to the synthetic chemist. Therefore, it is highly desirable to have enzymes available for the catalysis of these abiological reactions.
With the advent of robust expanded genetic code methodologies, it is now feasible to introduce a wide variety of unnatural amino acids into proteins. We envision that the time has come to use this breakthrough technology to create enzymes that contain abiological reactive groups as catalytic residue, for the catalysis of reactions that are not possible using canonical amino acids only.

The global aim of this project is the creation and application of designer enzymes with genetically encoded unnatural amino acids as catalytic residue for novel and new-to-nature catalysis.

The following research objectives are key to achieving the overall aim:
1. Achieving incorporation of unnatural amino acids containing organocatalytic side chains in proteins.
2. Creation of a library of novel designer enzymes containing unnatural amino acids as catalytic residue.
3. Application of these designer enzymes in catalysis of important reactions that have no equivalent in nature.
4. Directed evolution of designer enzymes featuring unnatural amino acids as catalytic residue.
5. Application of designer enzymes containing UAAs as catalytic residue in biocatalytic cascades.

This highly ambitious project combines frontier chemical and biochemical research and will deliver completely new classes of enzymes that can access new and previously unexplored parts of biocatalytic “reaction space”. In this way, this project will contribute to achieving the important societal goal of achieving greener and more sustainable approaches to chemical synthesis.

Host institution

Net EU contribution
€ 2 499 996,00
Broerstraat 5
9712CP Groningen

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Noord-Nederland Groningen Overig Groningen
Activity type
Higher or Secondary Education Establishments
Total cost
€ 2 499 996,00

Beneficiaries (1)