What is the problem being addressed? What are the overall objectives?
Life depends on a multitude of chemical reactions that we collectively call metabolism. Many of these reactions occur in defined sequences called metabolic pathways and are facilitated by a special type of proteins that are called enzymes. In most known metabolic pathways, we know which enzyme facilitates which reaction. However, our picture is still incomplete. First, cells contain hundreds of metabolites, which have not yet been identified and for which we don't know how they are synthesized. Second, there are still many proteins that look like enzymes, but for which we don't know the function. Third, some enzymes have been described to have functions that are likely not their primary functions.
In this project, we are tried to understand the function and the formation of hitherto unknown metabolites with a suspected role in cancer biology and beyond. Cancer cells need to survive and proliferate in situations where normal cells would die or stop growing. To account for these requirements, cancer cells undergo metabolic adaptations. Our enzyme of interest likely plays a role in the metabolic adaptation of a specific subset of cancers but seems to be dispensable for most normal cells. The overarching goal was to understand how the unknown metabolites are formed, how they are degraded, how they are linked with other metabolic pathways, and how they affect other metabolic functions in a cell.
Why is it important for society?
Many molecular changes have been identified in cancer and other diseases. Some of these changes can be modulated by small molecules that can eventually be developed into treatments for patients. This is a long and arduous path. However, the first step on this path is to understand what the molecular targets of these therapies do in normal and in cancer cells. Our research aims to do this and open new avenues for future therapies.
What did we find?
Four main oucomes were achieved in the course of this project
A We discovered the mechanism of formation and degradation of 4 hitherto unknown metabolites. We also found how these metabolites modify cellular metabolism.
B We found several hitherto unknown steps in the biosynthesis of a lipid called dolichol, which plays a key role in a protein maturation process called glycosylation.
C We discovered that the Parkinson's gene PARK7/DJ1 serves to degrade a hitherto unknown highly reactive metabolite that otherwise causes damage to proteins and metabolites. This opens the door to explorations of these changes in Parkinson’s disease.
D We discovered how a specific type of lipid is degraded in human cells.
