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Published on: February 16, 2022
Generating S-nitrosothiols from hemoglobin: mechanisms, conformational dependence, and physiological relevance.
Camille J Roche1, Maria B Cassera, David Dantsker
1Department of Physiology and Biophysics, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
The Journal of Biological Chemistry
|June 19, 2013
Summary
Hemoglobin (Hb) and nitrite generate nitric oxide (NO) via nitrite reductase. A proposed nitrite anhydrase (NA) reaction involving ferric hemes generates S-nitrosothiols, providing a source of exportable NO bioactivity from red blood cells (RBCs).
Area of Science:
- Biochemistry
- Physiology
- Nitric Oxide Signaling
Background:
- Hemoglobin (Hb) reacts with nitrite to produce nitric oxide (NO), a key signaling molecule.
- Existing mechanisms do not fully explain the in vivo bioactivity of NO derived from Hb and nitrite, particularly its export from red blood cells (RBCs).
- A proposed nitrite anhydrase (NA) reaction involving ferric heme-bound nitrite generating N2O3 has been suggested but faced questions regarding its physiological relevance.
Purpose of the Study:
- To investigate the physiological relevance and mechanism of the proposed nitrite anhydrase (NA) reaction.
- To demonstrate the formation of a functional N2O3 intermediate under near-physiological conditions.
- To explore the role of ferric heme sites in generating exportable NO bioactivity.
Main Methods:
- Studied reactions between NO, nitrite, and ferric hemes under near-physiological conditions.
- Characterized the properties of reaction intermediates.
- Investigated the formation of S-nitrosothiols (e.g., S-nitrosoglutathione) using ferric heme sites with nitrite and a reductant (L-cysteine).
Main Results:
- Demonstrated the formation of an intermediate with properties consistent with the proposed NA heme-bound N2O3.
- Showed that ferric heme sites, often considered detrimental, are functionally significant in partially oxygenated/methemoglobin states.
- Confirmed that ferric heme sites can generate S-nitrosothiols in the presence of nitrite and NO or L-cysteine.
Conclusions:
- Ferric heme sites in Hb can act as a nitrite anhydrase, producing N2O3 and facilitating NO export.
- This mechanism provides a source of RBC-derived and exportable bioactive NO, particularly in partially oxygenated/methemoglobin states.
- The findings highlight a novel functional role for ferric hemes in NO signaling beyond potential toxicity.
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