Engineered enzymes forge carbon-carbon and carbon-nitrogen bonds with high selectivity
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Researchers from the Manchester Institute of Biotechnology, including Dr. Zachary Birch-Price and professor Anthony Green, have developed a new family of engineered enzymes that can create several different types of chemical bonds used to build complex molecules. This work demonstrates how artificial enzymes can be adapted to carry out a broad range of carbon-carbon (C-C) and carbon-nitrogen (C-N) bond-forming reactions with high selectivity, offering new possibilities for biocatalysis.
Published in Nature Catalysis, the research addresses a long-standing challenge in chemistry: developing biological catalysts that can selectively construct complex molecular architectures. Carbon-carbon and carbon-nitrogen bonds are fundamental building blocks in many chemicals, pharmaceuticals and advanced materials.
"Biocatalysis has transformed our ability to carry out many chemical reactions using enzymes, but there are still important areas of chemistry that remain difficult to access. In this work, we show that artificial enzymes can be engineered to perform a wide variety of bond-forming reactions. What is particularly exciting is that the same underlying catalytic strategy can be adapted to work with many different reaction partners. This versatility gives us a foundation for developing new enzyme platforms capable of producing a wide range of valuable chemical structures," said Green, professor of chemical biology and director of the MIB.
To expand on the reaction pathways found in natural enzymes, the researchers engineered proteins containing a non-natural catalytic amino acid. This facilitated the development of a new enzyme class, termed allylic transferases, which form highly reactive imidazolium intermediates that could then be intercepted by a variety of carbon- and nitrogen-containing molecules, selectively producing a diverse range of products.
The team used directed evolution to improve enzyme performance. One evolved variant, known as ASB1.3, achieved more than 99% conversion in several reactions while delivering products with high stereochemical purity. In a preparative-scale reaction, the enzyme produced the target compound with 98% conversion.
A second enzyme variant, ASA1.5, enabled the formation of molecules containing all-carbon quaternary stereocenters, structures that can be challenging to synthesize selectively. In preparative-scale experiments, the enzyme achieved 98% conversion.
The researchers demonstrated that the engineered enzymes could work with a broad range of reaction partners, including substituted furans, indoles, pyrroles, cyanoesters, diketones, ketoesters, anilines and isatins. Across the reactions examined, the enzymes generated a single major product with no observable byproducts other than the released leaving group used for monitoring the reaction.
Expanding the biocatalysis toolbox
Structural analysis also provided new insights into how the enzymes achieve their selectivity. The team found evidence that a para-nitrophenol group released during the reaction remains in the enzyme active site and helps orient incoming reactants, contributing to stereoselective bond formation.
While further development will be needed before these enzymes can be applied more widely, the study expands the range of chemical transformations available through biocatalysis. It highlights how engineered protein catalysts can provide new ways to access molecular structures that are difficult to produce using established small-molecule catalysts.
First author Birch-Price said, "By combining enzyme engineering with non-natural catalytic chemistry, we were able to create a family of bond-forming enzymes new to the biocatalytic repertoire. We hope these findings will help guide the development of future enzyme platforms for selective chemical synthesis."
Publication details
Zachary Birch-Price et al, Protein-confined imidazolium intermediates enable diverse biocatalytic C–C and C–N bond formations, Nature Catalysis (2026). DOI: 10.1038/s41929-026-01587-8
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