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Peroxidases are enzymes that break down hydrogen peroxide in organisms. Since their discovery in 1998, the electron source of "peroxiredoxin 6-type" peroxidases for this reaction remained unclear. The research group of Professor Marcel Deponte at RPTU has now closed this knowledge gap. The researchers demonstrated in two model organisms – humans and malaria pathogens – that peroxiredoxin 6-type enzymes react rapidly with hydrosulfide, the anion of hydrogen sulfide. The study, funded by the German Research Foundation (DFG), was published in the journal "Advanced Science." The findings reveal a previously unknown connection between peroxide and sulfide metabolism.
For many years, the Deponte group has compared and characterized redox enzymes, including peroxidases, which enzymatically detoxify hydrogen peroxide or convert it into a signaling molecule. These enzymes require electrons, which they transfer from a reducing agent to hydrogen peroxide. Since 1998, one of the longstanding questions in the field has been which reducing agent peroxiredoxin 6-type peroxidases utilize.
During his PhD research in the Deponte lab, Lukas Lang showed that peroxiredoxin 6-type enzymes, unlike related peroxidases, do not react with common physiological reducing agents (published in 2023 in the journal ACS Catalysis). "The idea of testing hydrogen sulfide or sulfides, which are found in all living organisms, as reducing agents gained momentum when, in 2024, two other research groups independently discovered that peroxiredoxin 6-type peroxidases can react with hydrogen selenide," explains the biochemist from Kaiserslautern.
Peroxide metabolism meets sulfide metabolism
Hydrogen selenide and hydrogen sulfide share similar chemical properties. However, not all organisms with this widespread peroxidase type have a selenium metabolism, whereas all living organisms have a sulfide metabolism. Hydrogen sulfide is not only a smelly and potentially toxic gas. It also serves as a signaling molecule and occurs in its deprotonated form as sulfide in, for example, iron-sulfur clusters of enzymes. Laura Leiskau and Lukas Lang, first authors of the study, therefore investigated, initially out of pure curiosity, whether peroxiredoxin 6-type enzymes react with hydrogen sulfide.
"Our research showed that peroxiredoxin 6-type peroxidases in humans and the malaria parasite Plasmodium falciparum react extremely rapidly with hydrosulfide, the anion of hydrogen sulfide. As a result, hydrogen peroxide is reduced to water and hydrogen disulfide is formed as a potential source of persulfides. The latter are currently thought to have a protective function. Furthermore, we gained first insights into the intermediates of the unusual catalytic cycle of these enzymes," concludes doctoral student Laura Leiskau.
The Kaiserslautern working group has thus succeeded in demonstrating a possible novel enzymatic link between peroxide and sulfide metabolism, thereby contributing to a better understanding of persulfide biochemistry.
Enzymes from two model organisms deliver comparable results
To measure the rapid enzymatic reactions directly, Laura Leiskau used the so-called stopped-flow method for her research. In this method, the reaction partners, in this case the enzyme and its substrate, are mixed very quickly inside a spectrometer. If the different states of the enzyme under investigation have different fluorescence properties, possible changes during catalysis can be tracked in the range of thousandths of a second using a fluorescence detector.
Commercial peroxide solutions and corresponding sulfide salts of high purity served as sources of hydrogen peroxide and hydrosulfide. The required amounts of peroxiredoxin 6-type enzymes from human and the malaria parasite were recombinantly produced in harmless strains of the bacterium Escherichia coli and subsequently purified. "Humans and malaria parasites are evolutionarily unrelated and belong to completely different groups of eukaryotes. Since the results were highly comparable, we assume that hydrosulfide also reacts very quickly with other peroxiredoxin 6-type peroxidases," explains Marcel Deponte.
The project was funded by the DFG (DE 1431/19-1 project number 508372800). Laura Leiskau, Lea Bambach, and Marcel Deponte are members of the Graduate School 2737 STRESSistance.
Marcel Deponte
Comparative biochemistry
T: +49 631 205-3421
E: deponte[at]rptu.de
Lukas Lang, Laura Leiskau, Lea Bambach, Marcel Deponte (2025): H2S Is a Potential Universal Reducing Agent for Prx6-Type Peroxiredoxins; Advanced Science, https://doi.org/10.1002/advs.202507214
https://doi.org/10.1021/acscatal.2c04896
Symbolic representation of the reaction catalyzed by the peroxidase of the “Peroxiredoxin 6 type.”
Copyright: RPTU, AG Deponte
Professor Marcel Deponte and Laura Leiskau at a stopped-flow spectrofluorometer, as used in the rese ...
Quelle: Thomas Koziel
Copyright: RPTU, Thomas Koziel
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Symbolic representation of the reaction catalyzed by the peroxidase of the “Peroxiredoxin 6 type.”
Copyright: RPTU, AG Deponte
Professor Marcel Deponte and Laura Leiskau at a stopped-flow spectrofluorometer, as used in the rese ...
Quelle: Thomas Koziel
Copyright: RPTU, Thomas Koziel
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