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Boron-infusion turns protein into new-to-nature biocatalyst


A newly designed enzyme containing boron shows promising catalytic properties currently not found in nature. It could lead to applications in different fields, such as medicine and green chemistry.

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Enzymes drive essential biochemical reactions. Their unparalleled selectivity and efficiency, combined with a high sustainability and versatility, make that enzymes are increasingly applied as biocatalysts for the synthesis of high-value compounds, like pharmaceutical drugs. Still, the limited repertoire of catalytic activities displayed by natural enzymes challenges their potential to fully replace the organo-chemical catalysts currently in use by the chemical industry. Therefore, there is a need to design artificial enzymes with new-to-nature catalytic activities.

In the last few years, scientists have managed to create artificial enzymes by taking a small molecule catalyst and adding it into a non-catalytic protein scaffold.

Now, for the first time, researchers from the University of Groningen (The Netherlands) have merged boron with a protein scaffold, which has resulted in an enzyme that uses the boronic acid group with unique catalytic properties.

Boron biocatalyst

Boron is not used by nature as a catalyst at all, possibly because it only occurs in solid rock formations, so it is not easily accessible. However, boronic acid containing compounds are extensively used as catalysts in organic chemistry for constructing carbon-carbon bonds, and as reactive building blocks for making smart materials via self-assembly. However, organoboron catalysts generally suffer from a few important shortcomings: they exhibit only moderate activity, poor stereo selectivities and operate at environmentally unfriendly reaction conditions.  

“The advantage of putting boron in a protein scaffold is that you can get stereo selectivity and you can subsequently optimise catalytic properties via rounds of amino acid mutations and selection, a process named directed evolution”, explains Andy-Mark Thunnissen, protein crystallographer at the University of Groningen and co-author of the publication. A boron biocatalyst also operates under mild conditions, minimizing waste and environmental impact, compared to organoboron catalysts.

X-ray crystallography to validate the enzyme

In order to validate their boron designer enzyme, the team used several methods, including NMR spectroscopy, high-resolution mass spectroscopy and X-ray crystallography at the ESRF. The scientists needed crystal structures from the work done at the ESRF to guide the protein engineering efforts, to validate whether the designs work and to rationalize how the mutations improve catalytic properties..

They collected data at the fully automated beamline MASSIF-1: “For this kind of work we need to scan multiple crystals, so that we can choose the best resolution and the best data”, he says. “The efficiency and reliability of the automatic data collection workflows at MASSIF-1 certainly facilitated and accelerated our research”, he adds.


Close-up view of an active site showing  electron density at 1.72 Å resolution of a cyclic boronate-ester intermediate, obtained with X-ray diffraction data collected at the ESRF MASSIF-1 beamline. The observed intermediate supports the unique catalytic role of the boronic acid group in stereoselectively converting alpha-hydroxyketones to oximes. Credits: A. Thunnissen.

The results may open doors to possible industrial applications, from drug synthesis to sustainable energy production. According to Gerard Roelfes, who is the corresponding author on the paper, “we are not there yet, but the rapid developments in enzyme design and directed evolution, in combination with advanced computational and machine learning techniques, makes me confident that real life applications of designer enzymes for new-to-nature chemical reactions can be achieved in this decade”.


Longwitz, L. et al, Nature, 8 May 2024. DOI:10.1038/s41586-024-07391-3 

Text by Montserrat Capellas Espuny