Periodic Reporting for period 4 - NoMePaCa (Novel Metabolic Pathways in Cancer)
Période du rapport: 2022-11-01 au 2024-04-30
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.
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.
The work achieved during the funding period can be separated in two parts:
1. Discovery of key components of novel and known metabolic pathways
a) We found 4 novel metabolites, understood how they are formed and how they are degraded, and explored their role in cellular metabolism.
b) We discovered a hitherto unknown highly reactive metabolite that is formed from a key component of glycolysis, the central pathway for sugar metabolism. This metabolite avidly reacts with proteins and metabolites in cells and damages them. We also discovered that virtually all living organisms have an enzyme that degrades this reactive metabolite, thereby preventing damage. Interestingly, a deficiency in this protective pathway is known to cause early-onset Parkinson's disease. Future studies will need to reveal to what extent this type of damage contributes to Parkinson's disease in a wider range of patients.
c) We have found three new steps in the biosynthesis of a lipid called dolichol, which plays a key role in a type of protein maturation that is called glycosylation.
d) We have discovered a specific pathway that helps degrade a specific type of lipid.
2. Dissemination and publication
Results from the project were published in scientific journals and presented at scientific meetings, but results from the funding period will still continue to be published after the end of the funding period.
1. Discovery of key components of novel and known metabolic pathways
a) We found 4 novel metabolites, understood how they are formed and how they are degraded, and explored their role in cellular metabolism.
b) We discovered a hitherto unknown highly reactive metabolite that is formed from a key component of glycolysis, the central pathway for sugar metabolism. This metabolite avidly reacts with proteins and metabolites in cells and damages them. We also discovered that virtually all living organisms have an enzyme that degrades this reactive metabolite, thereby preventing damage. Interestingly, a deficiency in this protective pathway is known to cause early-onset Parkinson's disease. Future studies will need to reveal to what extent this type of damage contributes to Parkinson's disease in a wider range of patients.
c) We have found three new steps in the biosynthesis of a lipid called dolichol, which plays a key role in a type of protein maturation that is called glycosylation.
d) We have discovered a specific pathway that helps degrade a specific type of lipid.
2. Dissemination and publication
Results from the project were published in scientific journals and presented at scientific meetings, but results from the funding period will still continue to be published after the end of the funding period.
We have identified how the substrates of our enzyme of interest are formed in cells, and how they modulate cellular metabolism. Extensive explorations revealed that this pathway has surprisingly little influence on the growth of cancer cells. Yet, as anticipated in the 'perspectives' section, several findings likely play an important role in Parkinson's disease and metabolic disease. This includes:
1. A mechanistic link with a gene involved in the development of Parkinson's disease (PARK7/DJ1).
2. The discovery of a novel metabolic pathway required for the degradation of a specific type of lipids.
3. The biochemical pathway required for the synthesis of dolichol.
1. A mechanistic link with a gene involved in the development of Parkinson's disease (PARK7/DJ1).
2. The discovery of a novel metabolic pathway required for the degradation of a specific type of lipids.
3. The biochemical pathway required for the synthesis of dolichol.