Designer enzymes featuring unnatural amino acids as catalytic residue

2026-07-22

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.

Netherlands

2025-10-01