Title: 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. Here, 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 polysulfidesmore » 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.« less

Authors:

Vitvitsky, Victor ^[1]; Yadav, Pramod K. ^[1]; An, Sojin ^[1]; Seravalli, Javier ^[2]; Cho, Uhn-Soo ^[1]; Banerjee, Ruma ^[1]

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+ Show Author Affiliations

1. Univ. of Michigan Medical School, Ann Arbor, MI (United States)
2. Univ. of Nebraska, Lincoln, NE (United States)

Publication Date:

Fri Feb 17 00:00:00 EST 2017

Research Org.:

Argonne National Lab. (ANL), Argonne, IL (United States)

Sponsoring Org.:

National Inst. of Health

OSTI Identifier:

1351356

Grant/Contract Number:  

GM112455; DK111465

Resource Type:

Accepted Manuscript

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; crystal structure; heme; hemoglobin; hydrogen sulfide; oxidation-reduction (redox)