Technical University of Denmark: ERC Advanced Grant to understand enzyme stability

The European Research Council, set up by the European Union in 2007, is the premier European funding organisation for excellent frontier research. Every year, it selects and funds the very best, creative researchers of any nationality and age, to run projects based in Europe.

The ERC offers four core grant schemes: Starting, Consolidator, Advanced and Synergy Grants. To date, the ERC has funded nearly 10,000 researchers at various stages of their careers, and over 70,000 postdoctoral fellows, PhD students and other staff working in their research teams.

A new ERC project aims to improve our understanding of enzyme stability and broaden the field of potential applications for biocatalysis.

Professor John Woodley from DTU Chemical Engineering has received an Advanced Grant from ERC, the European Research Council. The grant of EUR 2.4 M will for the next five years fund research in enzymes and the effect on their stability when utilised in science and industry.

The enzyme-based industry is vast, but stability remains an issue. The reason behind it is a fundamental scientific question that remains unanswered. In nature, enzymes, which are proteins, catalyse the chemical processes needed for cells to function. Outside of nature, in science and industry alike, they perform the same functions, catalysing chemical processes to the benefit of the food industry, biotechnology, chemistry, and medicine.

However, In these practical but new-to-nature applications, enzymes lose their stability. They unfold, losing their structure and activity—and we do not know precisely how or why. That is a challenge, John Woodley explains, since we would like to use enzymes in many other environments as well:

“I think the opportunity for using enzymes is far greater than we have really achieved yet. There is an enormous potential that allows going into, for example, medium to low-priced chemical products. Today, the vast majority of chemicals are made using traditional chemical methods. Still, we can do much better than that, using enzyme-based catalysis to create more sustainable solutions. What we need to do is bring down the cost contribution of the enzymes. One part is producing the enzymes, but big enzyme-producing companies are experts at this, so we will not make big improvements to that. What we can do, however, is to get the enzymes to last for longer. And that is a question of stability.”

Several hypotheses
In his ERC project, John Woodley will test several hypotheses. Briefly put, contact with gasses and organic liquids and recycling processes all limit enzyme stability. For instance, supplying oxygen to a process will produce a gas-liquid interface. This will help achieve the desired reaction, but it is often damaging to the enzyme and ultimately will limit application. There could also be new ways of running reactors that we do not yet understand and, therefore, do not know how to utilise.

Usually, enzyme stability is measured after exposure to different temperatures or pH values. According to John Woodley, the effect of mixing, exposure to high concentrations of reactant and product, and dynamic gas-liquid or liquid-fluid interfaces is often overlooked, although they are common in most practical applications.

“We also need to improve the stability to move into new applications, lower-priced products, and chemicals. Even in cases where the stability is adequate today, we still don’t understand what causes the long-term stability loss. We move into a non-natural environment in many industrial processes, where we don’t know how the enzymes work. It is interesting to see how natures catalysts can work in non-natural environments and understand their mechanisms. Surely, there will be technical developments coming from this project. Still, it is also a fairly fundamental question to understand what goes on,” he says.

Improved equipment design
To that end, he will design new equipment mimicking the large-scale tanks and reactors as used today in the enzyme-based industry. The aim is also to devise new and improved designs for industrial equipment for better enzyme stability. Because maybe a new reactor design will pave the way for new applications, for instance, supplying oxygen differently.

Another potential benefit of the research is the ability to screen enzymes to remain stable in non-natural conditions and find the best-suited enzymes for a particular function.
Moreover, John Woodley claims, the true potential of biocatalysis remains far from being realised. It is also the primary reason that many novel uses of enzymes have yet to prove economically viable:

“The impact of this project will be that people doing protein engineering to improve enzymes will learn more about how to do that and to test for stability and identify potential problems. But this is not just about enzymes since enzymes are proteins. There are many other interesting applications of proteins, also as therapeutics. Much of what is learnt here will apply to other industries, where proteins are the products rather than the catalysts.”

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