Researchers have resolved a scientific puzzle that persisted for more than 25 years, identifying the source of electrons for a crucial class of enzymes that protect cells from damage. A team led by biochemists at the Rhineland-Palatinate Technical University of Kaiserslautern-Landau (RPTU) discovered that peroxiredoxin 6-type enzymes use hydrosulfide, a form of hydrogen sulfide, to neutralize toxic hydrogen peroxide. The study, published in the journal Advanced Science, demonstrates a fundamental and previously unknown link between the metabolism of peroxides and sulfides within living cells.
This finding fundamentally alters the scientific understanding of how organisms manage oxidative stress and cellular signaling. By identifying hydrosulfide as the key reactant, the research illuminates a novel biochemical pathway shared by a vast range of life, including humans and the parasite that causes malaria. The connection not only explains the basic function of a ubiquitous enzyme but also opens new avenues for exploring cellular processes and developing therapeutic strategies for diseases where this metabolic interplay is critical. The work provides a vital piece of the puzzle in the complex field of redox biology, which studies the transfer of electrons in cells.
An Enduring Enzymatic Question
Since their discovery in 1998, peroxidases of the peroxiredoxin 6 (PRDX6) type presented a frustrating enigma for biochemists. These enzymes were known to be highly efficient at breaking down hydrogen peroxide, a reactive oxygen species that can cause significant damage to cellular components if left unchecked. The chemical reaction requires a source of electrons, transferred from what is known as a reducing agent, to convert the peroxide into harmless water. For decades, however, the specific reducing agent that partners with PRDX6 enzymes remained elusive.
Previous investigations had systematically ruled out the usual suspects. Research from the same lab, conducted by doctoral student Lukas Lang, had already demonstrated that PRDX6 enzymes do not react with the common physiological reducing agents that other, related peroxidases typically employ. This lack of a known electron donor hindered a complete understanding of the enzyme’s role in the cell. It was clear that PRDX6 was important for detoxification, but the full cycle of its activity was a mystery. This knowledge gap left scientists unable to fully map the metabolic pathways involved in peroxide degradation, a process essential for cell survival.
The Pivotal Role of Hydrogen Sulfide
The breakthrough came when the research team, led by Professor Marcel Deponte, turned its attention to a seemingly unlikely candidate: hydrogen sulfide. This compound is widely known as a toxic gas with a characteristic rotten-egg smell. However, within the body, it also functions as a critical signaling molecule, similar to nitric oxide, and is involved in a wide array of cellular processes. Present in virtually all living organisms, hydrogen sulfide exists in equilibrium with its anion, hydrosulfide, in aqueous environments like the inside of a cell.
A Decisive Chemical Reaction
The researchers hypothesized that hydrosulfide could be the missing electron donor for PRDX6. This idea was bolstered by independent 2024 findings from other groups showing that the enzymes could react with hydrogen selenide, a compound with similar chemical properties to hydrogen sulfide. Using a technique called stopped-flow spectrofluorometry, Deponte’s team mixed the enzymes with hydrosulfide and observed the reaction. They found that the reaction was extremely rapid and efficient. The PRDX6 enzyme effectively used the electrons from hydrosulfide to reduce hydrogen peroxide to water, in the process forming hydrogen disulfide. This experiment provided the first direct evidence of an enzymatic link between the two metabolic pathways.
Findings Confirmed Across Distant Species
To determine if this newly discovered mechanism was a unique feature of one organism or a more fundamental process in biology, the scientists conducted their experiments on PRDX6 enzymes from two vastly different forms of life: humans and Plasmodium falciparum, the single-celled parasite that causes malaria. These two organisms are separated by over a billion years of evolution and represent entirely different branches of eukaryotic life. The fact that the enzymes from both species behaved in a nearly identical manner, reacting swiftly with hydrosulfide, provided powerful evidence that this pathway is a conserved mechanism.
Professor Deponte stated that because the results in humans and the malaria parasite were so comparable, it is highly likely that hydrosulfide reacts just as quickly with other peroxidases of the peroxiredoxin 6 type. This suggests the pathway is a widespread solution to the problem of peroxide detoxification across nature, highlighting a fundamental principle of biochemistry that had been overlooked until now. The discovery has significant implications for understanding the cellular biology of pathogens like Plasmodium, which must survive intense oxidative stress within their human hosts.
Implications for Health and Biotechnology
The discovery of this metabolic link is more than a simple biochemical curiosity; it has profound implications for medical science and biotechnology. Understanding how cells handle reactive molecules is central to understanding aging, stress, and a multitude of diseases. This new pathway provides researchers with a more complete map of the cell’s defensive and signaling networks, which could be leveraged for therapeutic benefit.
Targeting Disease and Understanding Stress
In the context of infectious diseases, this finding offers a potential new target. The malaria parasite’s reliance on this pathway for survival could be exploited to develop new drugs that disrupt its ability to neutralize oxidative stress. By inhibiting this specific enzymatic activity, it may be possible to weaken the parasite and make it more vulnerable to the host’s immune system. More broadly, the interplay between sulfide and peroxide metabolism may be relevant in other conditions characterized by high levels of oxidative stress, including cardiovascular and neurodegenerative diseases.
Future Research Directions
This foundational discovery opens up numerous avenues for future research. Scientists can now investigate how the availability of hydrogen sulfide within a cell affects its ability to cope with peroxide threats. The findings also contribute to a better understanding of the emerging field of persulfide metabolism, which explores how sulfide-containing molecules are used in cellular processes. The work by the RPTU team has not only answered a long-standing question but has also laid the groundwork for a new chapter in the study of cellular metabolism, promising deeper insights into the intricate chemical ballet that sustains life.
