Polysulfides link H2S to protein thiol oxidation

Antioxid Redox Signal. 2013 Nov 20;19(15):1749-65. doi: 10.1089/ars.2012.5041. Epub 2013 Jun 20.


Aims: Hydrogen sulfide (H2S) is suggested to act as a gaseous signaling molecule in a variety of physiological processes. Its molecular mechanism of action was proposed to involve protein S-sulfhydration, that is, conversion of cysteinyl thiolates (Cys-S(-)) to persulfides (Cys-S-S(-)). A central and unresolved question is how H2S-that is, a molecule with sulfur in its lowest possible oxidation state (-2)-can lead to oxidative thiol modifications.

Results: Using the lipid phosphatase PTEN as a model protein, we find that the "H2S donor" sodium hydrosulfide (NaHS) leads to very rapid reversible oxidation of the enzyme in vitro. We identify polysulfides formed in NaHS solutions as the oxidizing species, and present evidence that sulfane sulfur is added to the active site cysteine. Polysulfide-mediated oxidation of PTEN was induced by all "H2S donors" tested, including sodium sulfide (Na2S), gaseous H2S, and morpholin-4-ium 4-methoxyphenyl(morpholino) phosphinodithioate (GYY4137). Moreover, we show that polysulfides formed in H2S solutions readily modify PTEN inside intact cells.

Innovation: Our results shed light on the previously unresolved question of how H2S leads to protein thiol oxidation, and suggest that polysulfides formed in solutions of H2S mediate this process.

Conclusion: This study suggests that the effects that have been attributed to H2S in previous reports may in fact have been mediated by polysulfides. It also supports the notion that sulfane sulfur rather than sulfide is the actual in vivo agent of H2S signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Catalytic Domain
  • Cell Line
  • Cysteine / chemistry
  • Enzyme Activation / drug effects
  • Humans
  • Hydrogen Sulfide / chemistry*
  • Kinetics
  • Morpholines / chemistry
  • Organothiophosphorus Compounds / chemistry
  • Oxidation-Reduction
  • PTEN Phosphohydrolase / antagonists & inhibitors
  • PTEN Phosphohydrolase / chemistry
  • PTEN Phosphohydrolase / metabolism
  • Proteins / chemistry*
  • Proteins / metabolism*
  • Solutions
  • Sulfhydryl Compounds / chemistry*
  • Sulfides / chemistry*
  • Sulfides / pharmacology


  • GYY 4137
  • Morpholines
  • Organothiophosphorus Compounds
  • Proteins
  • Solutions
  • Sulfhydryl Compounds
  • Sulfides
  • polysulfide
  • PTEN Phosphohydrolase
  • sodium bisulfide
  • Cysteine
  • sodium sulfide
  • Hydrogen Sulfide