Researchers have solved a biochemical puzzle that has persisted for more than two decades, identifying the electron source for a crucial class of enzymes that neutralize harmful peroxides. A team at the Technical University of Kaiserslautern-Landau (RPTU) has demonstrated that peroxiredoxin 6-type enzymes are activated by hydrogen sulfide, a compound commonly known for its rotten-egg smell but that also functions as a vital signaling molecule in the body. This breakthrough forges a direct and previously unknown link between the metabolic pathways that manage peroxides and those that regulate sulfides, two fundamental processes for cellular health.
The discovery, detailed in the journal Advanced Science, fundamentally alters the understanding of how cells handle oxidative stress and intercellular communication. For years, scientists could not determine which molecule donated the necessary electrons to this family of peroxidases, hindering a complete picture of their function. By showing that hydrosulfide, the ionized form of hydrogen sulfide, readily fuels these enzymes in organisms as diverse as humans and the malaria parasite, the research provides a key missing piece in the study of redox biology. The finding has wide-ranging implications, from basic cell biology to the potential development of new therapeutic strategies for diseases like malaria.
An Enduring Biochemical Enigma
Cells constantly produce reactive oxygen species, such as hydrogen peroxide, as byproducts of normal metabolism. While these molecules play roles in cell signaling, high concentrations can cause significant damage to DNA, proteins, and lipids—a condition known as oxidative stress. To prevent this damage, organisms rely on a variety of antioxidant enzymes, including peroxidases, which specialize in converting hydrogen peroxide into harmless water. This enzymatic detoxification requires a source of electrons, which are taken from a reducing agent and transferred to the peroxide.
One particular class of these enzymes, the peroxiredoxin 6-type peroxidases, has been the subject of intense study since its discovery in 1998. While its function in breaking down peroxide was clear, the specific reducing agent that fueled this reaction remained elusive. The research group of Professor Marcel Deponte at RPTU has dedicated years to characterizing these enzymes. Previous work within the lab by doctoral researcher Lukas Lang had systematically tested common physiological reducing agents, confirming that peroxiredoxin 6 enzymes, unlike their relatives, did not react with them. This deepened the mystery and suggested that a less conventional electron donor was involved, leaving a significant knowledge gap in the field for nearly 26 years.
The Crucial Role of Sulfide
The investigation took a pivotal turn toward an unlikely candidate: hydrogen sulfide. Though widely known as a foul-smelling and toxic gas, hydrogen sulfide is also produced in small, controlled amounts within the body, where it acts as a gasotransmitter—a signaling molecule similar to nitric oxide that regulates processes like blood pressure and inflammation. In its ionized form, hydrosulfide, it is present in all living organisms and participates in the formation of essential structures like iron-sulfur clusters in other enzymes.
The idea to test sulfide as the electron donor was sparked by serendipity and astute scientific reasoning. In 2024, two independent research groups discovered that peroxiredoxin 6-type enzymes could react with hydrogen selenide, a chemical cousin of hydrogen sulfide. As Deponte’s team noted, selenium metabolism is not present in all organisms that have these peroxidases. However, sulfide metabolism is universal. This suggested that sulfide was a far more plausible and general-purpose partner for the enzyme across different species. This hypothesis provided a new and promising path forward to finally solving the long-standing puzzle of the enzyme’s function.
Methods and Confirmation
To validate their hypothesis, the researchers embarked on a series of precise experiments to observe the enzyme’s behavior in the presence of sulfide. Their work provided definitive evidence of the interaction and clarified the chemical steps involved in the process.
Model Organisms
A key strength of the study was its use of enzymes from two evolutionarily distant organisms: humans and Plasmodium falciparum, the single-celled parasite that causes the most severe form of malaria. Demonstrating that the sulfide-driven reaction occurred in both human and parasitic enzymes underscored its fundamental importance and suggested that this is a deeply conserved biological mechanism. This dual-organism approach immediately broadens the relevance of the findings, positioning them as a core principle of biochemistry rather than a species-specific quirk.
Measuring a High-Speed Reaction
The reaction between the peroxidase and hydrosulfide proved to be incredibly fast, requiring specialized equipment to capture. Researcher Laura Leiskau, a doctoral student in Deponte’s lab, employed a technique known as the stopped-flow method. This approach involves mixing the enzyme and its substrate together in fractions of a second inside a spectrometer, allowing for the real-time measurement of rapid chemical changes. The stopped-flow data revealed that the peroxiredoxin 6 enzymes react with hydrosulfide at an extremely high velocity, confirming that the interaction is efficient enough to be biologically relevant.
Reaction Products
The experiments successfully mapped the entire catalytic cycle. The enzyme facilitates the transfer of electrons from hydrosulfide to hydrogen peroxide. This process reduces the harmful peroxide to water, effectively detoxifying it. In the process, the hydrosulfide is oxidized to form hydrogen disulfide. This byproduct is itself a significant molecule, as it is considered a potential source of persulfides, which are chemical species currently believed to have protective antioxidant functions within cells. The team was also able to gain initial insights into the intermediate steps of this unique catalytic process.
Connecting Two Metabolic Worlds
The most profound implication of this research is the establishment of a direct, enzymatic bridge between peroxide and sulfide metabolism. For decades, these two critical cellular systems were studied largely in parallel. Peroxide metabolism is central to the field of oxidative stress and redox signaling, concerning the management of reactive oxygen species generated by aerobic life. Sulfide metabolism, meanwhile, is tied to bioenergetics, the sulfur cycle, and its own distinct class of cellular signaling. This discovery merges these two worlds, showing they are not just concurrent but deeply intertwined.
This newly found link suggests a more integrated cellular network for managing reactive molecules and transmitting signals than was previously understood. The peroxiredoxin 6 enzyme now emerges as a key intersection point, a molecular hub where the cell can modulate signals from both peroxide and sulfide pathways. It provides a mechanism by which changes in sulfide levels could directly impact a cell’s ability to handle oxidative stress, and vice versa. This integrated perspective will allow scientists to better understand how cells maintain homeostasis in a complex chemical environment.
Future Research and Potential Applications
The identification of this fundamental biochemical pathway opens up numerous avenues for future investigation. It stands to reshape our understanding of cellular signaling and the metabolic regulation of reactive compounds across a wide range of organisms. By closing a major knowledge gap, the research provides a new foundation for exploring how cells respond to both internal and external stimuli.
Furthermore, the findings may have significant therapeutic potential. The crucial role of the enzyme in the malaria parasite Plasmodium falciparum is particularly noteworthy. Understanding the intricacies of the parasite’s redox biology, including how it protects itself from oxidative stress, could expose new vulnerabilities. If this enzymatic pathway is essential for the parasite’s survival, it could become a target for novel antimalarial drugs. More broadly, as the link between oxidative stress, sulfide signaling, and various human diseases becomes clearer, this discovery could inform strategies for treating a range of conditions where these pathways are dysregulated.
