Structural and Mechanistic Insights into Hemoglobin-catalyzed Hydrogen Sulfide Oxidation and the Fate of Polysulfide Products
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 weremore »
- Authors:
- Publication Date:
- Research Org.:
- Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
- Sponsoring Org.:
- National Institutes of Health (NIH)
- OSTI Identifier:
- 1351356
- Resource Type:
- Journal Article
- Journal Name:
- Journal of Biological Chemistry
- Additional Journal Information:
- Journal Volume: 292; Journal Issue: 13; Journal ID: ISSN 0021-9258
- Publisher:
- American Society for Biochemistry and Molecular Biology
- Country of Publication:
- United States
- Language:
- ENGLISH
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES
Citation Formats
Vitvitsky, Victor, Yadav, Pramod K., An, Sojin, Seravalli, Javier, Cho, Uhn-Soo, and Banerjee, Ruma. Structural and Mechanistic Insights into Hemoglobin-catalyzed Hydrogen Sulfide Oxidation and the Fate of Polysulfide Products. United States: N. p., 2017.
Web. doi:10.1074/jbc.M117.774943.
Vitvitsky, Victor, Yadav, Pramod K., An, Sojin, Seravalli, Javier, Cho, Uhn-Soo, & Banerjee, Ruma. Structural and Mechanistic Insights into Hemoglobin-catalyzed Hydrogen Sulfide Oxidation and the Fate of Polysulfide Products. United States. doi:10.1074/jbc.M117.774943.
Vitvitsky, Victor, Yadav, Pramod K., An, Sojin, Seravalli, Javier, Cho, Uhn-Soo, and Banerjee, Ruma. Fri .
"Structural and Mechanistic Insights into Hemoglobin-catalyzed Hydrogen Sulfide Oxidation and the Fate of Polysulfide Products". United States. doi:10.1074/jbc.M117.774943.
@article{osti_1351356,
title = {Structural and Mechanistic Insights into Hemoglobin-catalyzed Hydrogen Sulfide Oxidation and the Fate of Polysulfide Products},
author = {Vitvitsky, Victor and Yadav, Pramod K. and An, Sojin and Seravalli, Javier and Cho, Uhn-Soo and Banerjee, Ruma},
abstractNote = {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.},
doi = {10.1074/jbc.M117.774943},
journal = {Journal of Biological Chemistry},
issn = {0021-9258},
number = 13,
volume = 292,
place = {United States},
year = {2017},
month = {2}
}
Works referenced in this record:
H2S Signals Through Protein S-Sulfhydration
journal, November 2009
- Mustafa, A. K.; Gadalla, M. M.; Sen, N.
- Science Signaling, Vol. 2, Issue 96
Biosynthesis and Reactivity of Cysteine Persulfides in Signaling
journal, December 2015
- Yadav, Pramod K.; Martinov, Michael; Vitvitsky, Victor
- Journal of the American Chemical Society, Vol. 138, Issue 1
Relative Contributions of Cystathionine β-Synthase and γ-Cystathionase to H 2 S Biogenesis via Alternative Trans-sulfuration Reactions
journal, June 2009
- Singh, Sangita; Padovani, Dominique; Leslie, Rachel A.
- Journal of Biological Chemistry, Vol. 284, Issue 33
Averaged kick maps: less noise, more signal…and probably less bias
journal, August 2009
- Pražnikar, Jure; Afonine, Pavel V.; Gunčar, Gregor
- Acta Crystallographica Section D Biological Crystallography, Vol. 65, Issue 9
The structure of Aquifex aeolicus sulfide:quinone oxidoreductase, a basis to understand sulfide detoxification and respiration
journal, June 2009
- Marcia, M.; Ermler, U.; Peng, G.
- Proceedings of the National Academy of Sciences, Vol. 106, Issue 24
Features and development of Coot
journal, March 2010
- Emsley, P.; Lohkamp, B.; Scott, W. G.
- Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 4
Human Methionine Synthase Reductase, a Soluble P-450 Reductase-like Dual Flavoprotein, Is Sufficient for NADPH-dependent Methionine Synthase Activation
journal, July 2001
- Olteanu, Horatiu; Banerjee, Ruma
- Journal of Biological Chemistry, Vol. 276, Issue 38
PHENIX: a comprehensive Python-based system for macromolecular structure solution
journal, January 2010
- Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor
- Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2, p. 213-221
H 2 S Biogenesis by Human Cystathionine γ-Lyase Leads to the Novel Sulfur Metabolites Lanthionine and Homolanthionine and Is Responsive to the Grade of Hyperhomocysteinemia
journal, March 2009
- Chiku, Taurai; Padovani, Dominique; Zhu, Weidong
- Journal of Biological Chemistry, Vol. 284, Issue 17
Three enzymatic activities catalyze the oxidation of sulfide to thiosulfate in mammalian and invertebrate mitochondria: Reactions of mitochondrial sulfide oxidation
journal, June 2008
- Hildebrandt, Tatjana M.; Grieshaber, Manfred K.
- FEBS Journal, Vol. 275, Issue 13
Organization of the Human Mitochondrial Hydrogen Sulfide Oxidation Pathway
journal, September 2014
- Libiad, Marouane; Yadav, Pramod Kumar; Vitvitsky, Victor
- Journal of Biological Chemistry, Vol. 289, Issue 45
Reactive cysteine persulfides and S-polythiolation regulate oxidative stress and redox signaling
journal, April 2014
- Ida, T.; Sawa, T.; Ihara, H.
- Proceedings of the National Academy of Sciences, Vol. 111, Issue 21
XDS
journal, January 2010
- Kabsch, Wolfgang
- Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2
Biogenesis of reactive sulfur species for signaling by hydrogen sulfide oxidation pathways
journal, June 2015
- Mishanina, Tatiana V.; Libiad, Marouane; Banerjee, Ruma
- Nature Chemical Biology, Vol. 11, Issue 7
Kinetics of oxidation of aqueous sulfide by oxygen
journal, June 1972
- Chen, Kenneth Y.; Morris, J. Carrell
- Environmental Science & Technology, Vol. 6, Issue 6
Phaser crystallographic software
journal, July 2007
- McCoy, Airlie J.; Grosse-Kunstleve, Ralf W.; Adams, Paul D.
- Journal of Applied Crystallography, Vol. 40, Issue 4