Structural and Mechanistic Insights into Hemoglobincatalyzed Hydrogen Sulfide Oxidation and the Fate of Polysulfide Products

Authors

Victor Vitvitsky, University of Michigan Medical School
Pramod K. Yadav, University of Michigan Medical School
Sojin An, University of Michigan Medical School
Javier Seravalli, University of Nebraska-LincolnFollow
Uhn-Soo Cho, University of Michigan Medical School
Ruma V. Banerjee, University of Michigan Medical CenterFollow

Document Type

Article

Date of this Version

2017

Citation

THE JOURNAL OF BIOLOGICAL CHEMISTRY VOL. 292, NO. 13, pp. 5584–5592

Comments

© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

DOI 10.1074/jbc.M117.774943

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 oxidizes H₂S 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 α-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.