disease treatments – Lightsources.org

“Molecular glue” could be used to control activity of harmful proteins

Proteins do most of the work in our body’s cells. But when a protein is too active or does not function properly, it can lead to disease or other health problems.

Researchers from the University of Toronto have discovered a molecule, CLEO4-88, that acts as a ‘molecular glue,’ binding together two proteins to inactivate one of them. The finding – enabled by the Canadian Light Source (CLS) at the University of Saskatchewan – points to the possibility of one day treating disease by controlling the activity of harmful proteins.Video: Hijacking cell’s natural machinery to help treat diseases

Molecular glues typically stick together two proteins that would not normally interact, marking one of them for destruction. In this study, researcher Chetan Chana and colleagues discovered that instead marking a protein for destruction, CLEO4-88 inactivated it. The team’s findings are published in the journal Nature Chemical Biology.

The high-powered X-rays at the CLS enabled the researchers to see that CLEO4-88 stuck two proteins together and slowed down the activity of one of them (ACAA1). While ACAA1 – which is involved in breaking down fats inside cells – was not destroyed, its activity was reduced. This mechanism could potentially be leveraged to control some triple negative breast cancers, where ACAA1 activity has been shown to be elevated.

Read more on the CLS website

Image: Molecular glue – crystal

Credit: CLS

Identifying 3D structure of enzymes by University of Guelph researchers key first step in harnessing alterations for disease treatments.

For decades, pharmaceutical companies have been using bacteria found in soil and water to chemically convert steroids into effective treatments for human diseases. One example is cortisol, which is used to treat asthma and skin rashes. But how bacteria convert steroids is not fully understood.

Now a research team from the University of Guelph has taken a significant step forward in answering that question. Using the Canadian Light Source (CLS) at the University of Saskatchewan, Dr. Stephen Seah and colleagues have determined the 3D structures of steroid-transforming enzymes from Proteobacteria (also called Pseudomonadota), a large, diverse family of gram-negative bacteria named after Proteus – the shape-shifting Greek sea god.Video: Understanding bacteria’s role in transforming steroids to pharmaceuticals

Studying the 3D structure of these enzymes, which Seah says would be impossible without the ultrabright X-ray source of the CLS, is key to understanding how this Proteobacteria chemically transforms steroids – such as bile acids – which are typically resistant to being changed.

Seah and his colleagues found that the bacteria have evolved to transform steroids as a means to obtain carbon and energy for their own growth. However, he says, these transformations can be harnessed to chemically alter steroids into compounds that we can use for disease treatments; a discovery that will help advance future pharmaceutical development.

“If we understand the process, we can manipulate other bacteria to produce novel compounds that may have medicinal properties,” says Seah. “I think my work helps fill in this gap of knowledge.” The team’s research findings were published recently in both the Journal of Biological Chemistry and Biochemistry.

This new research, says Seah, also opens the door to exploring the potential of other enzymes in bacteria to change the chemical structure of steroids. “In other words, one could create steroids with diverse chemical structures using the many steroid-modifying enzymes that bacteria produced to alter naturally occurring steroids,” he says. “Some of these modified steroids may have therapeutic properties.”

Read more on the CLS website

Image: Protein structure

Credit: CLS