Structural and mechanistic insights into hemoglobincatalyzed hydrogen sulfide oxidation and the fate of polysulfide products

Victor Vitvitsky, Pramod K. Yadav, Sojin An, Javier Seravalli, Uhn Soo Cho, Ruma Banerjee

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Hydrogen sulfide is a cardioprotective signaling molecule but is toxic at elevated concentrations. Red blood cells can synthesize H2S but, lacking organelles, cannot dispose of H2S via the mitochondrial sulfide oxidation pathway. We have recently shown that at high sulfide concentrations, ferric hemoglobin oxidizesH2S to a mixture of thiosulfate and iron-bound polysulfides in which the latter species predominates. Here, we report the crystal structure of human hemoglobin containing low spin ferric sulfide, the first intermediate in heme-catalyzed sulfide oxidation. The structure provides molecular insights into why sulfide is susceptible to oxidation in human hemoglobin but is stabilized against it in HbI, a specialized sulfide-carrying hemoglobin from a mollusk adapted to life in a sulfide-rich environment. We have also captured a second sulfide bound at a postulated ligand entry/exit site in the-subunit of hemoglobin, which, to the best of our knowledge, represents the first direct evidence for this site being used to access the heme iron. Hydrodisulfide, a postulated intermediate at the junction between thiosulfate and polysulfide formation, coordinates ferric hemoglobin and, in the presence of air, generated thiosulfate. At low sulfide/heme iron ratios, the product distribution between thiosulfate and iron-bound polysulfides was approximately equal. The iron-bound polysulfides were unstable at physiological glutathione concentrations and were reduced with concomitant formation of glutathione persulfide, glutathione disulfide, and H2S. Hence, although polysulfides are unlikely to be stable in the reducing intracellular milieu, glutathione persulfide could serve as a persulfide donor for protein persulfidation, a posttranslational modification by which H2S is postulated to signal.

Original languageEnglish (US)
Pages (from-to)5584-5592
Number of pages9
JournalJournal of Biological Chemistry
Volume292
Issue number13
DOIs
StatePublished - Mar 31 2017

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Hydrogen Sulfide
Sulfides
Oxidation
Thiosulfates
Hemoglobins
Iron
Heme
Glutathione
Hemoglobin Subunits
polysulfide
Glutathione Disulfide
Mollusca
Poisons
Post Translational Protein Processing
Molecular Structure
Organelles
Molecular structure
Blood
Erythrocytes
Crystal structure

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Structural and mechanistic insights into hemoglobincatalyzed hydrogen sulfide oxidation and the fate of polysulfide products. / Vitvitsky, Victor; Yadav, Pramod K.; An, Sojin; Seravalli, Javier; Cho, Uhn Soo; Banerjee, Ruma.

In: Journal of Biological Chemistry, Vol. 292, No. 13, 31.03.2017, p. 5584-5592.

Research output: Contribution to journalArticle

Vitvitsky, Victor ; Yadav, Pramod K. ; An, Sojin ; Seravalli, Javier ; Cho, Uhn Soo ; Banerjee, Ruma. / Structural and mechanistic insights into hemoglobincatalyzed hydrogen sulfide oxidation and the fate of polysulfide products. In: Journal of Biological Chemistry. 2017 ; Vol. 292, No. 13. pp. 5584-5592.
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