The Catalysts of Life

Enzyme Research

They keep humans, animals and plants alive: As biocatalysts, enzymes play a key role in every cell. And it is this characteristic that makes them so fascinating to an interdisciplinary Team searching for biocatalysts beyond the boundaries of the divisions – and finding them.

“When we first started,” recalls Dr. André Pütz, “we waited and waited for the enquiries to come.” While the advantages of using enzymes were indeed already known, centralized contact persons, people ready to help out in both word and deed, were lacking. “When the first calls came in, we rejoiced inwardly. Finally, we would be able to show that it really worked!” Over the course of the project, the number of enquiries grew steadily, and the requirements with them. “Now, we have to pay careful attention to the order in which the enquiries come through, because we have more than we can deal with simultaneously.”

There is a very good reason for the demand for the services offered by the Biotransformation Platform: the project team has been extremely successful. The collaboration, through Nimbus, between colleagues from Pharmaceuticals, Crop Science und Technology Services was thus greatly simplified and correspondingly intensified. The result: all enquiries can be processed rapidly and straightforwardly. And in almost 80 percent of cases, the team is able to come up with an enzyme that can work as a catalyst for the reaction in question. Pütz, who heads the Biochemistry & Biocatalysis group of Bayer Technology Services, also points out that, “These days, we are pretty fast.” And that is also important for the team. “When our colleagues come to us, they know they can save time – which also means saving money.”

Dr. André Pütz and his colleagues share is to find, isolate and characterize new biocatalysts
The task that Dr. André Pütz and his colleagues share is to find, isolate and characterize new biocatalysts. Their success
has been impressive. For almost 80 percent of all enquiries, the team is able to find an enzyme that catalyzes the desired reaction

The colleagues he is talking about work for Pharmaceuticals and Crop Science, and are constantly on the lookout for new chemical compounds in new areas of application, both for the development of alternative substances for animal and human medicines, and for active substances for use in plant protection. However, the molecules that the researchers deal with are becoming increasingly complex. And this complexity puts ever-growing demands on the requirements for catalysts, as well. This is where enzymes, as “reaction helpers,” can play a pivotal role.

This role is often associated with what are known as stereocenters. These are found in practically all new substances – sometimes more than once. If a stereocenter is present, then the molecules of the substance, despite having the same structure, exhibit diametrically opposite behavior relative to one another. This means that they are non-superposable. Basically, says Pütz, you can think of the two molecules as being like two hands: at first glance, they are the same, but they are not identical.

What makes this particularly challenging is that the mirror-image molecules can have different effects. Thus – when developing a new active substance, for example – it is crucial to be able to produce only one of these so-called enantiomers. The other has to be separated out as soon as possible. “And that,” says Pütz with a smile, “is where enzymes come in.”

Biocatalysts in the brewery: Enzymes are created in germinated malt, and these transform the starches contained in the grain into maltose during the brewing process. Malt is what gives the beer its fullness of flavor and color.

These biological catalysts can differentiate between the left hand and the right. So, if one wants to alter only one of the two hands, enzymes can carry out the task with extreme precision. “Of course, we’re not doing anything that our colleagues in the chemical sector can already do well,” Pütz explains. For especially complex molecules – synthesizing hormones, for example – biocatalysts are indispensable. “There are many reactions that are only possible at all by using biocatalysis.”

But how can enzymes that might be used in a chemical synthesis be identified? To answer this question, and to be able to use biocatalysts throughout the entire Bayer Group, an interdisciplinary team has been working to establish an enzyme collection. They have been doing this since 2013 as part of the cross-company Biotransformation Platform, part of the larger Nimbus initiative, which gives the Bayer Technology Services experts a clear overview of exactly what the divisions require. At the same time, they keep a constant eye on their ultimate goal: to ensure that enzymes are employed as standard tools for chemical syntheses. And together with their colleagues in the divisions, they can already look back on many successes

This is also confirmed by Dr. Daniel Götz, who works in substance development at Pharmaceuticals. By using enzymes in his project, he was able to benefit from the experience of the project team. More specifically, a purely chemical step in a synthesis was replaced by an enzymatic step. The result: the desired reaction took place with significantly higher specificity and better yield. Götz was pleased with the result: “The people at Bayer Technology Services made a decisive contribution to our success.” And they did so all the way from identifying the right enzyme to implementing it on a 400-litre scale. “In the end, everything worked, despite a very challenging schedule.”

“Biotransformation is a great example of how life science synergies at Bayer stimulate both R&D and our innovation culture.”

Kemal Malik

Bayer AG Board Member responsible for innovation

It is these successes that make the entire team proud. What’s more, the specified goals have all been achieved, some even over-achieved. Pütz sees the close, trusting collaboration between the participants as an important factor in their mutual success. Dr. Olaf Queckenberg, head of Global Chemical & Pharmaceutical Development at Pharmaceuticals, backs him up, concluding that, “The experts from Bayer Technology Services bundle our expertise and the available enzyme libraries – and have taken it well beyond the boundaries of the divisions. That’s where the added value lies.”

It goes almost without saying that such results are the consequence of hard work. But for Pütz, the fun he has in the process is almost as important. “For me, that’s a major part of my motivation.” The same sentiment is expressed – repeatedly and conspicuously – by the other biocatalysis experts at Bayer Technology Services.

To maintain a regular exchange of ideas and information, the specialists have set up their own community, comprising mainly chemists, biochemists, biologists, biotechnologists, molecular biologists and bioprocess engineers spread across seven different Bayer sites.

Research Success with Nimbus

Science thrives on the exchange of experiences. And there are plenty of opportunities for this when it comes to the health of people, animals and plants. The Bayer Group is now focusing more closely on these interfaces, and launched the Nimbus initiative to this end back in 2012. Aiming to interlink the life sciences more closely, the company has provided 30 million euros for new research projects. The researchers are working on such issues as epigenetics, high-throughput screening for drug discovery, and biotransformations. Their objective: to more intensively exchange acquired knowledge beyond the boundaries of location and technical specialization, and to further improve the quality of research.

Twice a year, they meet to discuss the current state of their work. Pütz is convinced that this community is also an important success factor. “We share a common goal, and that creates a connection.” And as relaxed as they may be with one another personally, they take their work very seriously indeed. “So far, we have been able to identify new ideas and fields of application at every meeting,” he says. “And together, we are looking for – and discovering – the right solutions.”

It may be that this strong interaction is the true secret of their success, Pütz suggests. Then he quickly adds, “And, of course, the very great desire that it really will work out.” But it is “incredibly satisfying to come up with and demonstrate applicable, practicable solutions together with one’s colleagues: See, it really works!”

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