The results, reported in the journal Nature Chemical Biology, open the door to creating more effective antioxidant therapies to combat neurodegenerative diseases, cancer, and aging-related disorders, the researchers say.
"For decades, we have relied on the notion that antioxidants generally function as free radical scavengers," says senior author Jianhua Zhang, PhD, professor and chair of the Department of Physiology at the University of Kentucky College of Medicine. "Our study reveals a completely new mechanism for how antioxidants can work, which will guide us to develop more potent therapeutic agents for antioxidant-based therapies."
Free radicals, also known as reactive oxygen species (ROS), are natural byproducts of cellular metabolism. However, an overabundance of ROS can cause oxidative stress, damaging DNA, proteins, and lipids, and contributing to a range of diseases. For that reason, cells employ various antioxidant defense mechanisms to protect against oxidative damage.
Zhang's team focused on a key player in antioxidant defenses known as peroxiredoxin 6 (Prx6), an antioxidant enzyme that has shown great potential as a therapeutic target for neurodegenerative conditions such as Alzheimer's and Parkinson's diseases. Although its importance is clear, the mechanism by which Prx6 combats oxidative stress has remained elusive.
To unravel this mystery, the researchers used a combination of advanced biochemical and biophysical techniques, including X-ray crystallography, to determine the precise molecular architecture of Prx6. The high-resolution structure revealed that Prx6 does not function as a traditional free radical scavenger, as previously thought. Instead, it operates as a molecular gatekeeper, forming a shield that physically intercepts and blocks the damaging ROS from attacking cellular targets.
The study offers a new concept of "molecular shielding" as a distinct mechanism for antioxidant defense. It's a significant paradigm shift from the traditional notion of free radical scavenging and highlights the importance of spatial and temporal regulation of ROS in cells, says Zhang.
The team also uncovered a regulatory switch within the Prx6 structure, which explains how it can be activated in response to oxidative stress. This discovery opens new avenues for designing small molecule activators of Prx6, which could potentially enhance cellular antioxidant defenses and mitigate oxidative damage in disease conditions.
"This work provides a solid foundation for the rational design and development of novel therapeutic strategies aimed at boosting antioxidant defenses and treating diseases associated with oxidative stress," Zhang says.
