First artificial enzyme with non-biological catalytic sites created

First artificial enzyme with non-biological catalytic sites created

New compound prevents amyloid formation to fight Alzheimer’s disease The sidechain attaches itself to the LmrR protein, by what are called supramolecular bonds – that is, bonds formed as a result of the enzyme’s interactions with the transcription factor. The researchers explain, “Its position is determined by the interaction with the protein. From this position, we determined where the p-aminophenylalanine should be inserted into the protein to create an active site. From my experience in organic chemistry, I knew the potential utility of this aniline side chain for catalysis and envisioned that it would be possible to combine it with copper catalysis.” Using this idea, the researchers built a new enzyme which had highly selective activity for the Michael addition. This time around, the researchers adapted this same protein, but then added in the copper complex to the bacterial protein, before inserting the p-aminophenylalanine. The latter’s aniline chain combined with copper to act as a powerful catalyst for this reaction. Copper is a well-known transitional metal catalyst due to the presence of variable oxidation states, allowing them to accept and donate electrons with ease. Both of these sites cooperate to catalyze the reaction partners for the Michael addition reaction, a common organic reaction that is used to create bonds between carbon atoms. However, just putting both of them into a molecule doesn’t work, because they counteract each other at too close distances. Says Roelfes, “They both have to be in the right position to efficiently and selectively catalyse this reaction.” Admittedly, the enzyme is a relatively slow one. Roelfes explains, “The enzyme is not yet fast enough for practical use but, with standard techniques such as directed evolution, this could be improved.” The concept The important thing they achieved is that they showed a proof of concept. Two abiological or unnatural catalysts were brought together for the first time to build a completely new enzyme. They feel that this could serve as a launchpad for the synthesis of many different types of new enzymes. The importance of the technique is that it was designed to be used by ordinary chemists, though it involves molecular biology methods for the incorporation of the unnatural amino acids. This has made it possible for the team to continue to produce new synthetic enzymes. The major use of unnatural amino acids in enzyme synthesis so far was to try to elucidate the mechanisms behind their catalytic properties, and to understand how the enzyme function was linked to its molecular structure. Roelfes and his researchers have expanded this to include the use of novel amino acids via genetic code, within enzymes. He says, “To me, the generation of new-to-nature enzymes is the most exciting option.” The addition of unnatural amino acids to a protein to create a new enzyme could be adopted to make many more, covering the complete range of standard chemical reactions. This would change the face of chemistry reactions, making them more environmentally friendly and also reducing the energy inputs. Journal reference: Drienovská, I., Roelfes, G. Expanding the enzyme universe with genetically encoded unnatural amino acids. Nat Catal (2020). https://doi.org/10.1038/s41929-019-0410-8



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