The promise of peroxiredoxin

It’s that latter feature that has attracted recent interest, as a team from Oregon State University (OSU) has produced the first detailed, atomic-level images of peroxiredoxin using X-ray crystallography. These images have answered questions about the protein and could offer a new tactic for a class of antibiotics. Arden Perkins was lead author on the study. The work was done at OSU in collaboration with Andrew Karplus, a distinguished professor of biochemistry in the OSU College of Science.

As explained by Perkins, “Peroxiredoxins are found in animals, plants and bacteria, and are proteins that are crucial for cell survival. The main function of peroxiredoxins is to eliminate hydrogen peroxide in cells by converting it to water. This toxin is a byproduct of normal cell metabolism, and hydrogen peroxide has to be removed so it doesn’t damage the cell. If peroxiredoxin doesn’t do its job, cells will die.”

With the new images, the team also learned by watching the protein’s chemistry that if it’s restrained and loses mobility, it also loses its function, which in turn can lead to cell death. Even better, the images also showed that there are specific regions on bacterial peroxiredoxins that differ from those found in humans, which could offer a target that would shut down peroxiredoxin’s function only in bacteria and kill the invading cells.

“A common strategy for drug design is to block the active site of the protein of interest. However, this is difficult with peroxiredoxins because the active site is nearly identical between those in humans and the ones in pathogens,” explains Perkins. “We present evidence in this work that it is possible to target non-active site regions unique to bacterial peroxiredoxin that would prevent the proteins from switching between conformations and therefore trap the bacterial peroxiredoxins in an inactivated state.”

He notes that these proteins “cycle between two different forms, one that is catalytically active and can perform the chemistry of converting peroxide to water, and one that is ‘locally unfolded’ where a portion of the protein is unwound and is inactive. The active form of peroxiredoxins are all very similar but the inactive form is quite different, and the conformational changes the protein undergoes between them are therefore also different.”

Perkins tells DDNews that “one exciting thing about this idea is that many different regions of this protein could be targeted, meaning that this basic strategy of preventing conformation change could in fact give rise to numerous classes of antibiotics with distinct chemistry and structure.” With the growing issue of antibiotic resistance, an approach that could offer not just one but several new options for treating drug-resistant bacteria is welcome news. According to the U.S. Centers for Disease Control and Prevention, there are some 2 million infections resulting from antimicrobial-resistant bacteria in the United States every year, with an annual associated economic burden of $20 billion.

According to Perkins, “The next step for this work will be to apply knowledge of peroxiredoxin structure and function to screen drug leads and identify candidate compounds. We’ve already begun this process.”

The study, which was performed in collaboration with the OSU Department of Chemistry and the Wake Forest School of Medicine, is titled “Peroxiredoxin Catalysis at Atomic Resolution” and was published in Structure. The National Science Foundation, the National Institutes of Health and the U.S. Department of Energy supported this work.