New link between peroxide and sulfide metabolism discovered - Success in peroxidase research at RPTU
Peroxidases break down hydrogen peroxide in organisms. For enzymes of the "peroxiredoxin 6 type", it has been unclear since their discovery in 1998 where the electrons for this reaction come from. Professor Marcel Deponte's research group at RPTU has now closed this knowledge gap. The researchers used two model organisms - humans and malaria pathogens - to show that peroxiredoxin-6 enzymes react rapidly with hydrogen sulphide. Hydrogen sulphide is the anion of hydrogen sulphide. The study, funded by the German Research Foundation (DFG), has been published in the journal "Advanced Science". The findings establish a new link between peroxide and sulphide metabolism.
Professor Marcel Deponte's group has been comparing and characterizing redox enzymes for many years, including peroxidases, which enzymatically detoxify hydrogen peroxide or convert it into a signal molecule. To do this, the enzymes require electrons, which they transfer from a reducing agent to hydrogen peroxide according to the "give and take" principle. The question of which reducing agent peroxidases of the peroxiredoxin 6 type use has been one of the unsolved mysteries in the field of research since 1998.
As part of his doctorate in the Deponte working group, Lukas Lang was able to show that, unlike similar peroxidases, peroxiredoxin 6 enzymes do not react with common physiological reducing agents (published in 2023 in the journal ACS Catalysis). "The idea of testing hydrogen sulphide or the sulphides found in all living organisms as reducing agents gained momentum when two other research groups independently discovered in 2024 that peroxidases of the peroxiredoxin 6 type can react with hydrogen selenide," explains the biochemist from Kaiserslautern.
Peroxide metabolism meets sulphide metabolism
On the one hand, selenium and hydrogen sulphide have similar chemical properties. However, not all organisms with this widespread peroxidase type have a selenium metabolism, whereas all living organisms have a sulphide metabolism. Hydrogen sulphide is not only a smelly and potentially toxic gas. It also serves as a signaling molecule and occurs in deprotonated form as a sulfide in iron-sulfur centers of enzymes, among others. Laura Leiskau and Lukas Lang, first author and first author of the study, therefore investigated, originally out of pure curiosity, whether peroxiredoxin 6 enzymes react with hydrogen sulfide.
"Our research showed that peroxidases of the human peroxiredoxin 6 type and the malaria pathogen Plasmodium falciparum react extremely quickly with hydrogen sulphide, the anion of hydrogen sulphide. This reduces hydrogen peroxide to water and forms hydrogen disulphide as a potential source of persulphides. The latter is currently ascribed a protective function. We were also able to gain initial insights into the intermediate stages of the unusual catalysis cycle of these enzymes," concludes doctoral student Laura Leiskau.
Ultimately, the Kaiserslautern working group has succeeded in demonstrating a possible enzymatic link between peroxide and sulphide metabolism for the first time, thus contributing to a better understanding of persulphide metabolism.
Enzymes from two model organisms provide comparable results
In order to measure the rapid enzymatic reactions directly, Laura Leiskau used the so-called stopped-flow method for her research work. This involves mixing the reaction partners, in this case the enzyme and its substrate, very quickly in a spectrometer. If the different states of the enzyme under investigation have different fluorescence properties, possible changes in the course of catalysis can be tracked with time resolution in the range of thousandths of a second using a fluorescence detector.
Commercial peroxide solutions and corresponding sulphide salts of high purity were used as sources of hydrogen peroxide and hydrogen sulphide. The researchers were able to produce the required quantities of peroxiredoxin 6 enzyme from humans and malaria pathogens recombinantly in harmless strains of the bacterium Escherichia coli and then purify them. "Humans and malaria parasites are not evolutionarily related and belong to completely different groups of eukaryotes. As the results were very comparable, we assume that hydrogen sulphide also reacts very quickly with other peroxidases of the peroxiredoxin 6 type," 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.
The current study:
Lukas Lang, Laura Leiskau, Lea Bambach, Marcel Deponte (2025): H2SIs a Potential Universal Reducing Agent for Prx6-Type Peroxiredoxins;Advanced Science, https://doi.org/10.1002/advs.202507214
The pioneering studies of the working group mentioned in the text:
Lang L, Wolf AC, Riedel M, Thibol L, Geissel F, Feld K, Zimmermann J, Morgan B, Manolikakes G, and Deponte M. (2023) Substrate promiscuity and hyperoxidation susceptibility as potential driving forces for the co-evolution of Prx5-type and Prx6-type 1-Cys peroxiredoxin mechanisms. ACS Catalysis 13:3627-43. doi.org/10.1021/acscatal.2c04896
Scientific contact:
Professor Marcel Deponte
Comparative Biochemistry
T: 0631 205-3421
E: deponte[at]rPTU.de