Collaboration’s exciting discovery could be novel drug target

Thursday, 5 April 2012

A first-class collaboration between AstraZeneca and academia, Karolinska Institute, has resulted in a breakthrough discovery published in the Journal of Biological Chemistry. The collaboration, supported by grants from AstraZeneca and from the Swedish Research Council, has discovered a completely new enzyme system, which metabolises a drug in a fat cell. AstraZeneca is now close to answering the question about how its thrombin inhibitors are metabolised in the body—something that has eluded researchers for a decade.

Senior Principal Scientist Tommy B. Andersson says the result of the work with professor Magnus Ingelman-Sundberg and others at Stockholm’s Karolinska Institutet, is “…potentially one of the key findings of my scientific career. We have been looking for over 10 years to try to understand which system in the cell activates our drug. We have known about the reaction since 1973 but we could not identify which enzyme was involved.”

The enzyme system reducing the chemical structure amidoxime, which is an important component of thrombin inhibitors and several other drugs, was unknown when thrombin inhibitors were developed.

The collaboration discovered that the protein MOSC2 is a key enzyme in an electron chain, which has a role in the process of cell differentiation, lipid synthesis, as well as binding and activating the AstraZeneca compounds. The enzyme system is active in liver and fat cells although its composition has been unknown until now.

With the help of novel tools and expertise from AstraZeneca, the Karolinska Institutet was able to overcome a major challenge to identify the system. “It was impossible to purify it because it just fell apart. It was like looking for a needle in a haystack… and the needle was very sensitive!” said Dr Tommy Andersson.

He explained further, “This enzyme sits in the cell in the mitochondria, which is the power station in cells, producing a lot of energy, and is obviously important for lipid metabolism. If we knock out this enzyme we can see that it changes the lipid profile in a cell. We are still investigating it in more detail to evaluate its impact. We need further study to assess how useful it can be.”