Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Enzyme designers: Simulation of the AsqJ enzyme opens up new options for pharmaceutical chemistry

18.04.2018

Practically all biochemical processes involve enzymes that accelerate chemical reactions. A research team from the Technical University of Munich (TUM) has now for the first time deciphered the molecular mechanism of the enzyme AsqJ. They see potential applications in the production of pharmaceutically active molecules, for example.

Without enzymes, nature would come to a standstill. These tiny molecules accelerate biochemical reactions or make them possible in the first place. But how does this happen on a molecular level? "Understanding the exact function of enzymes is one of the greatest challenges of modern biochemistry," says Ville Kaila, Professor of Computational Biocatalysis at the Technical University of Munich.


Natural (left) and modified AsqJ. While a valine is incorporated at position 72 in the natural (blue) enzyme, the modified form possesses an isoleucine (red) at position 72.

Sophie Mader / TUM


Sophie Mader and Prof. Ville Kaila; on the screens the simulation of the two AsqJ variants.

Andreas Battenberg / TUM

The research team led by Ville Kaila and Michael Groll, Professor of Biochemistry at the Technical University of Munich, have, for the first time, deciphered the mechanism of the enzyme aspoquinolone J (AsqJ), a dioxygenase that activates carbon bonds with oxygen.

One enzyme – many reactions

The enzyme AsqJ is particularly exciting as it catalyzes a cascade of chemical reactions that ultimately lead to the formation of antibacterial compounds. It was discovered only a few years ago in the Aspergillus nidulans fungus.

The researchers combined different methods to uncover the secrets held within the enzyme: First, Alois Bräuer and Prof. Michael Groll used X-ray crystallography to determine the three-dimensional atomic structure of the molecule. Sophie Mader and Ville Kaila then used this information to carry out quantum mechanical simulations on its biochemical processes.

Elucidating the secrets of AsqJ with simulations

"Our calculations illustrate how the enzyme catalyzes the formation of quinolone alkaloid," reports Kaila. "Tiny details have amazing effects: A slight change in the substrate, like the removal of a small chemical group, is sufficient to practically stop the reaction."

Next, the team computationally designed a new variant of the enzyme that catalyzes the formation of quinolone alkaloids with the modified substrate. This new enzyme was experimentally produced in bacteria and tested for its functionality. “The results were impressive: the expected reaction took place after only a few seconds,” recalls Bräuer.

Computational design of new compounds

“This experiment demonstrates that our methodology works and is also suited to represent the functionality of other enzymes at the molecular level,” says Ville Kaila. Enzyme design is still at a basic level, but it has enormous potential. In the future, we could aim to computationally design medical drugs, for example.

“The work demonstrates that our methodology is accurate and also well suited to study the functionality of other enzymes at the molecular level,” says Ville Kaila. Enzyme design is still basic research – but it has enormous potential. An aim of future research will be to design enzymes in a computer to, for example, produce new drugs.

Publication:

S. L. Mader, A. Bräuer, M. Groll, V. R. I. Kaila
Catalytic mechanism and molecular engineering of quinolone biosynthesis in dioxygenase AsqJ. Nature Communications 9(1), 1168 (2018) – DOI: 10.1038/s41467-018-03442-2

Further information:

The research was funded by the European Research Council (ERC), the German Research Foundation (DFG), the Collaborative Research Centers SFB 1035 and SFB 749 and the Cluster of Excellence Integrated Protein Science Munich (CIPSM). The project received further support as part of the research cooperation between the TUM and the King Abdullah University of Science and Technology (KAUST). The crystal structures were determined in cooperation with the synchrotron source of the Paul Scherrer Institute in Villigen (Switzerland). The computer simulations were carried out in cooperation with the Leibniz Computer Center of the Bavarian Academy of Sciences.

Contact:

Prof. Ville R. I. Kaila
Technical University of Munich
Professorship of Computational Biocatalysis
Tel.: +49 89 289 13612
E-Mail: ville.kaila@ch.tum.de

Weitere Informationen:

http://www.compbio.ch.tum.de/ Website of Prof. Kaila’s group
http://www.biochemie.ch.tum.de/ Website of Prof. Groll’s group
https://www.nature.com/articles/s41467-018-03442-2 Original publication
https://www.tum.de/nc/en/about-tum/news/press-releases/detail/article/34577/ Press release at tum.de

Dr. Ulrich Marsch | Technische Universität München

More articles from Life Sciences:

nachricht Microscope measures muscle weakness
16.11.2018 | Friedrich-Alexander-Universität Erlangen-Nürnberg

nachricht Good preparation is half the digestion
16.11.2018 | Max-Planck-Institut für Stoffwechselforschung

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: UNH scientists help provide first-ever views of elusive energy explosion

Researchers at the University of New Hampshire have captured a difficult-to-view singular event involving "magnetic reconnection"--the process by which sparse particles and energy around Earth collide producing a quick but mighty explosion--in the Earth's magnetotail, the magnetic environment that trails behind the planet.

Magnetic reconnection has remained a bit of a mystery to scientists. They know it exists and have documented the effects that the energy explosions can...

Im Focus: A Chip with Blood Vessels

Biochips have been developed at TU Wien (Vienna), on which tissue can be produced and examined. This allows supplying the tissue with different substances in a very controlled way.

Cultivating human cells in the Petri dish is not a big challenge today. Producing artificial tissue, however, permeated by fine blood vessels, is a much more...

Im Focus: A Leap Into Quantum Technology

Faster and secure data communication: This is the goal of a new joint project involving physicists from the University of Würzburg. The German Federal Ministry of Education and Research funds the project with 14.8 million euro.

In our digital world data security and secure communication are becoming more and more important. Quantum communication is a promising approach to achieve...

Im Focus: Research icebreaker Polarstern begins the Antarctic season

What does it look like below the ice shelf of the calved massive iceberg A68?

On Saturday, 10 November 2018, the research icebreaker Polarstern will leave its homeport of Bremerhaven, bound for Cape Town, South Africa.

Im Focus: Penn engineers develop ultrathin, ultralight 'nanocardboard'

When choosing materials to make something, trade-offs need to be made between a host of properties, such as thickness, stiffness and weight. Depending on the application in question, finding just the right balance is the difference between success and failure

Now, a team of Penn Engineers has demonstrated a new material they call "nanocardboard," an ultrathin equivalent of corrugated paper cardboard. A square...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

“3rd Conference on Laser Polishing – LaP 2018” Attracts International Experts and Users

09.11.2018 | Event News

On the brain’s ability to find the right direction

06.11.2018 | Event News

European Space Talks: Weltraumschrott – eine Gefahr für die Gesellschaft?

23.10.2018 | Event News

 
Latest News

Purdue cancer identity technology makes it easier to find a tumor's 'address'

16.11.2018 | Health and Medicine

Good preparation is half the digestion

16.11.2018 | Life Sciences

Microscope measures muscle weakness

16.11.2018 | Life Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>