One enzyme’s structure may hold the key to new treatments for a variety of diseases: diabetes, cancer, neurodegenerative disorders, heart disease. Without knowing its structure, researchers have not been successful in developing inhibitor drugs to address the protein’s connection to various conditions through activating the inflammatory pathway. Now, from St. Louis University, scientists have been able to determine the enzyme’s structure.
"In the past, people have studied this complex enzyme, like a black box, without knowing what is inside," explained Sergey Korolev, PhD. "Now that we have discovered the structure, we can see every atom. This allows us to visualize what is happening with this protein. It is a completely new level of insight."
The enzyme is calcium-independent phospholipase A2β (iPLA2β), which was first discovered more than 20 years ago for its role in type 1 diabetes, then again ten years ago for its role in neurodegenerative disorders. In addition to “iPLA2β,” the enzyme is also referred to as PARK14 in connection to genetic mutations in patients with Parkinson’s disease.
“For example, inherited mutations in this gene were identified in patients with early onset Parkinson's,” Korolev explained.
Korolev and many other scientists are interested in iPLA2β because of its connection to the inflammatory response, a mechanism known to be at the foundation of multiple diseases. Past studies show that iPLA2β cleaves phospholipids in the cell membrane and responds to injury by triggering the immune response.
But without knowing iPLA2β’s molecular structure, researchers couldn’t answer important questions: How is iPLA2β activated during injury? How does it get shut down (deactivating the inflammatory response)?
Korolev and other scientists from St. Louis University were finally able to determine iPLA2β’s molecular structure via x-ray crystallography. What they found was different than what researchers had anticipated.
"Before we had the structure, people didn't have good tools to study this enzyme," Korolev said. “Now, the 3D structure gives us a clear hypothesis for how it is responsible for action in different cellular compartments and tissues.”
"There is a growing amount of genetic work that links iPLA2β to neurodegenerative disease, and physicians and scientists worldwide are now interested in its function," explained MD/PhD student Konstantin Malley. "We are still a long way from treating patients, but I would like them to know that the structure is a large step between genetics and developing targeted therapies for treatment.”
The present study was published in the journal Nature Communications.