Glutaredoxins Rapidly Reduce Glutathione Hydroper‐ and Polysulfides
- 1Department of Chemistry Comparative Biochemistry RPTU Kaiserslautern Kaiserslautern Germany
- 2Max‐Planck‐Institute for Polymer Research Mainz Germany
- 3Department of Redox Molecular Medicine Tohoku University Graduate School of Medicine Sendai Japan
Abstract
Hydropersulfides have gained attention as excellent biochemical nucleophiles and membrane‐protective radical scavengers. They form perthiyl radicals, which terminate radical chain reactions through self‐recombination, yielding polysulfides. It is currently unknown exactly how polysulfides are subsequently reduced. Using stopped–flow kinetic measurements in combination with mass spectrometry, we show that the model class I glutaredoxin from Plasmodium falciparum (PfGrx) rapidly reduces the polysulfides glutathione trisulfide (GS3G) and tetrasulfide (GS4G), yielding glutathionylated PfGrx and the corresponding glutathione hydropersulfide (GSSH) and hydrotrisulfide (GS3H). The second‐order rate constants of these reductions ≥107 M−1s−1 are even slightly higher than for glutathione disulfide (GSSG). In contrast, PfGrx was inactive or only moderately active toward cystine or cysteine trisulfide. GSSH and GS3H are further reduced by PfGrx with second‐order rate constants on the order of 106−107 M−1s−1, yielding glutathionylated PfGrx and hydrogen sulfide (H2S) or hydrogen disulfide (H2S2), respectively. Thus, glutaredoxins specifically recognize the glutathione moiety of glutathione (hydro)per/polysulfides. Since reduced glutathione (GSH) rapidly reduces glutathionylated glutaredoxins, glutathione (hydro)per/polysulfides are efficiently converted to GSSG and H2S or the corresponding hydrogen polysulfides. As a consequence, the steady‐state concentration of glutathione (hydro)per/polysulfides should be tightly controlled in subcellular compartments containing active glutaredoxins and high GSH concentrations.
Related
- Structural analysis of human alpha-class glutathione transferase A1-1 in the apo-form and in complexes with ethacrynic acid and its glutathione conjugate
- Enzymatic/Mitochondrial Import Bottleneck in Sepsis with Possible Extensions to DIC: IV Glutathione and Hinokitiol as Potential Therapeutic Candidates
- Unveiling the Molecular Basis of Silver(I) Sequestration by Glutathione: Stoichiometry, Stability and Structure at Neutral pH
- The glutathione S-transferase gene LaGSTU6 promotes somatic embryogenesis in a recalcitrant lily genotype by regulating scales redox homeostasis.
- Isoenzyme-specific determination of glutathione peroxidase activity in cell lysates and GPX1/GPX4-HiBiT cellular target engagement
BibTeX
@article{reinert2026glutaredoxins,
title = {{Glutaredoxins Rapidly Reduce Glutathione Hydroper‐ and Polysulfides}},
author = {Philipp Reinert and Seiryo Ogata and Laura Leiskau and Sernur Sena Yildiz and Takaaki Akaike and Uladzimir Barayeu and Marcel Deponte},
journal = {Angewandte Chemie (International Ed. in English)},
year = {2026},
month = sep,
doi = {10.1002/anie.1222129},
url = {https://doi.org/10.1002/anie.1222129},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Glutaredoxins Rapidly Reduce Glutathione Hydroper‐ and Polysulfides
AU - Philipp Reinert
AU - Seiryo Ogata
AU - Laura Leiskau
AU - Sernur Sena Yildiz
AU - Takaaki Akaike
AU - Uladzimir Barayeu
AU - Marcel Deponte
PY - 2026
DA - 2026/09/21
JO - Angewandte Chemie (International Ed. in English)
DO - 10.1002/anie.1222129
UR - https://doi.org/10.1002/anie.1222129
AB - Hydropersulfides have gained attention as excellent biochemical nucleophiles and membrane‐protective radical scavengers. They form perthiyl radicals, which terminate radical chain reactions through self‐recombination, yielding polysulfides. It is currently unknown exactly how polysulfides are subsequently reduced. Using stopped–flow kinetic measurements in combination with mass spectrometry, we show that the model class I glutaredoxin from Plasmodium falciparum (PfGrx) rapidly reduces the polysulfides glutathione trisulfide (GS3G) and tetrasulfide (GS4G), yielding glutathionylated PfGrx and the corresponding glutathione hydropersulfide (GSSH) and hydrotrisulfide (GS3H). The second‐order rate constants of these reductions ≥107 M−1s−1 are even slightly higher than for glutathione disulfide (GSSG). In contrast, PfGrx was inactive or only moderately active toward cystine or cysteine trisulfide. GSSH and GS3H are further reduced by PfGrx with second‐order rate constants on the order of 106−107 M−1s−1, yielding glutathionylated PfGrx and hydrogen sulfide (H2S) or hydrogen disulfide (H2S2), respectively. Thus, glutaredoxins specifically recognize the glutathione moiety of glutathione (hydro)per/polysulfides. Since reduced glutathione (GSH) rapidly reduces glutathionylated glutaredoxins, glutathione (hydro)per/polysulfides are efficiently converted to GSSG and H2S or the corresponding hydrogen polysulfides. As a consequence, the steady‐state concentration of glutathione (hydro)per/polysulfides should be tightly controlled in subcellular compartments containing active glutaredoxins and high GSH concentrations.
SN - 1433-7851
SN - 1521-3773
ER -