Breaking the rules of chemistry unlocks new reaction

Scientists have broken the rules of enzyme engineering to unlock a new method for creating chemical reactions that could unlock a wide range of new applications – from creating new drugs to food production.

In their paper published today in Nature Catalysis, Professor Francesca Paradisi and Dr. Martina Contente of the University of Nottingham and the University of Bern show a new method to produce chemical molecules more efficiently through a new one step reaction in the enzyme.

Any textbook on enzymes will report on how the catalytic amino acids in any given enzyme family are highly conserved, they are in fact a signature of the type of chemistry an enzyme can do. Variations do occur and in some cases, if the replacing amino acid is similar, both can be found in significant proportion in Nature, but others can be much less common and are found only in a limited number of species.

“In this study we have explored an untouched area of enzyme engineering and modified the a key catalytic residue in the active site of an enzyme” adds Professor Paradisi, “Previously it was thought that doing this would cause a loss of activity of the enzyme but we have found this is not the case when this biocatalyst is used in a synthetic direction and in fact challenging but very useful molecules can now be made under mild conditions which could be easily scaled up and replicated commercially for use in a wide range of products.”

To change the substrate scope of an enzyme the approach has generally been to mutate the residues involved in substrate recognition, whether through rational design or directed evolution, leaving always untouched the catalytic ones.

The mutant variant of an acyl transferase enzyme was rapidly created and while the native biocatalyst would work with alcohols and linear amines, the mutant work with thiols and much more complex amines too. The research demonstrated that indeed the new variant has lost the ability to hydrolyse esters, but for synthetic applications, where an ester or other functional groups need to be made (thioesters and amides) and not cleaved, this is in fact a major advantage.

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