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Eva's essay on Artificial Metalloenzymes

Extreme conditions, such as high temperatures, are needed for production of pharmaceuticals and other important chemicals, to obtain the desired product and higher yields of the product. However, in the face of climate change, we call for a transformation of industrial production. A possible solution for a greener environment could be a shift to a greener, more sustainable catalysis that is performed in milder conditions and creates less waste.

The most challenging are reactions that don’t occur in Nature. The first step towards a greener catalytic chemistry for catalysis of unnatural reactions was made by the introduction of transition metals as catalysts (catalysts lower the high temperatures needed for the reaction to occur). Palladium is one of the most common metal catalysts. The research on palladium and the formation of carbon-carbon bonds it catalyses, an extremely difficult and sought after reaction in the field of organic chemistry, brought the researchers the 2010 Nobel prize in Chemistry. However, the downside of metal catalysts is that they won't give us selectivity and cause harmful effects when released into the environment. The field of classic catalytic chemistry is still lacking selectivity, but above all, sustainability.

The increasingly popular approach of industrial production of compounds is the use of enzymes. In essence, enzymes work at a lock-and-key principle. By this principle, they ensure selectivity by leading the reaction giving us the exact product we are looking for. Moreover, we can tweak the activity of enzymes. We start with one enzyme and using directed evolution – a process developed by Frances Arnold and awarded with Nobel prize in 2018 – we are actually speeding up the evolution process and making enzymes more selective or even changing the reaction they catalyse. The major setback of enzymes is they are massively inefficient when it comes to the catalysis of unnatural reactions, unlike metal catalysts.

In the Jarvis group at the University of Edinburgh, we are working on the catalysis of unnatural reactions with metals. But without the adverse effect of inorganic metal catalysts and possible recycling of the metal catalyst by creating artificial metalloenzymes – catalysts of unnatural reactions.

Artificial metalloenzymes are created by combining a protein and metal catalyst. The protein acts as a frame and creates the environment for catalysis, making a mold to build the shape of the product we need. The metal is the one that triggers the reaction. We are currently working with a protein that by itself does not act as an enzyme, but has a large hydrophobic tunnel, which can bind hydrophobic compounds. Hydrophobic compounds are important in the production of pharmaceuticals and their production presents a challenge in classic catalytic chemistry.

The biggest challenge we are facing is binding the metal into the protein. 20 different amino acids are the building blocks of proteins of all organisms. Here we are using a novel method, where we, besides 20 usual amino acids, use unnatural amino acids. Unnatural amino acids are those that are not present in proteins across organisms. The unnatural amino acid we are using has a particular quality – it binds metal ions. Therefore, when the metal ions are added to the protein, they are bound to the unnatural amino acid in the hydrophobic tunnel of the protein. This is how we make our artificial metalloenzymes. Artificial metalloenzyme then performs specific reactions at room temperature.

The new technology we are using could be the future of catalytic chemistry.

Francis Crick was fascinated by of the more striking generalizations of biochemistry – how 20 amino acids are, with minor reservations, the same throughout Nature. Proteins built of just 20 amino acids catalyse all the known natural reactions. The possibilities of using countless unnatural amino acids are infinite.

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