Chemists create new-to-nature enzymes with boronic acid

Enzymatic reactions are more sustainable than classical chemical reactions.

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Boronic acid has been a staple in organic chemistry for many years despite its absence in any organism. According to Gerard Roelfes, a professor at the University of Groningen, it leads to unique chemical reactions not typically found in nature.

Roelfes and his team engineered an enzyme with boronic acid at its reactive center and used directed evolution to enhance its selectivity and catalytic power. Additionally, enzymatic reactions offer a more sustainable alternative to traditional chemical reactions, as they occur at lower temperatures and do not require toxic solvents.

The significance of boron in organic chemistry goes back several decades and was acknowledged with a Nobel Prize for Chemistry in 1979. While the use of boron as a catalyst has gained interest in recent years, its application in the chemical industry remains limited.

According to Roelfes, boron catalysis presently suffers from slow reaction rates and is not well-suited for enantioselective reactions, which are crucial for producing chiral molecules with specific pharmaceutical benefits. This limitation poses a challenge in selectively generating the desired molecular structure, particularly in the pharmaceutical sector, where the distinct “hands” of chiral molecules can have varying effects.

“To make this possible, we set out to introduce boron into an enzyme. Our group has a long history of designing enzymes that don’t exist in nature,” said Roelfes.

University of Groningen chemists introduced an artificial amino acid containg boron into an enzyme.
University of Groningen chemists introduced an artificial amino acid containg boron into an enzyme. Illustration: Roelfes Lab.

The Roelfes group successfully utilized an expanded genetic code to incorporate a non-natural amino acid featuring a reactive boronic acid group into an enzyme. This breakthrough approach allows for the precise determination of the amino acid’s placement in a protein at the DNA level.

Once the enzyme with the boronic acid at its reactive center was created, directed evolution techniques were employed to enhance its efficiency, leading to accelerated catalysis.

“Furthermore, by placing the boronic acid in the chiral context of an enzyme, we were able to achieve highly enantioselective catalysis,” said Roelfes. The reaction shows how to harness boron’s catalytic power in enzymes.

Utilizing enzymes for the production of organic compounds is crucial for the pharmaceutical industry. As part of the industry’s focus on more sustainable drug manufacturing methods, biocatalysis is being explored as a substitute for traditional chemical processes.

The University of Groningen is actively involved in advancing this initiative, with multiple research groups within the Faculty of Science and Engineering dedicated to developing biocatalytic solutions for the chemical industry. Professor Roelfes and his team are particularly focused on enhancing their boronic acid enzymes and pioneering the creation of novel enzymes not found in nature.

Journal reference:

  1. Lars Longwitz, Reuben B. Leveson-Gower, Henriëtte J. Rozeboom, Andy-Mark W. H. Thunnissen & Gerard Roelfes. Boron catalysis in a designer enzyme. Nature, 2024; DOI: 10.1038/s41586-024-07391-3

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