Catalytic generation of N2O3 by the concerted nitrite reductase and anhydrase activity of hemoglobin
Abstract
Nitrite reacts with deoxyhemoglobin to form nitric oxide (NO) and methemoglobin. Though this reaction is experimentally associated with NO generation and vasodilation, kinetic analysis suggests that NO should not be able to escape inactivation in the erythrocyte. We have discovered that products of the nitrite-hemoglobin reaction generate dinitrogen trioxide (N2O3) via a novel reaction of NO and nitrite-bound methemoglobin. The oxygen-bound form of nitrite-methemoglobin shows a degree of ferrous nitrogen dioxide (Fe(II)-NO2*) character, so it may rapidly react with NO to form N2O3. N2O3 partitions in lipid, homolyzes to NO and readily nitrosates thiols, all of which are common pathways for NO escape from the erythrocyte. These results reveal a fundamental heme globin- and nitrite-catalyzed chemical reaction pathway to N2O3, NO and S-nitrosothiol that could form the basis of in vivo nitrite-dependent signaling. Because the reaction redox-cycles (that is, regenerates ferrous heme) and the nitrite-methemoglobin intermediate is not observable by electron paramagnetic resonance spectroscopy, this reaction has been 'invisible' to experimentalists over the last 100 years.
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Altered RBC structure and signalling may restrict the export of NO to vascular tissues, thereby reducing vasodilatory responses despite adequate nitrite levels.
“Altered RBC structure and signalling may also restrict the export of NO to vascular tissues, thereby reducing vasodilatory responses despite adequate nitrite levels [56,128,263].”
From Dietary Nitrate-Rich Vegetables as Natural Modulators of Health: Mechanisms and Benefits in Ageing Populations (2026) · cites this paper as [263]
The formation of N2O3 in the red blood cell via an anhydrase reaction involving Hb, NO, and nitrite constitutes a possible pathway to preserve NO bioactivity.
“As discussed previously in section IIB2, the formation of N2O3 in the red blood cell via an anhydrase reaction involving Hb, NO, and nitrite (69) constitutes a possible pathway to preserve NO bioactivity (367).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [69]
Several proposed mechanisms explain how nitrite-derived bioactivity can be exported from the red blood cell, generally involving either a compartment model with submembrane localization or formation of another nitrogen oxide such as a nitrosothiol or N2O3.
“Several proposed mechanisms have been constructed to explain how nitrite-derived bioactivity can be exported from the red blood cell and these generally involve either a compartment model with submembrane localization of the reaction allowing for inefficient free NO escape, or the formation of another nitrogen oxide such as a nitrosothiol or N2O3 that can get out of the red blood cell and carry NO”
From Mechanisms of nitrite bioactivation (2014) · cites this paper as [47]
Another possibility is that nitrite binds to MetHb which subsequently reacts with NO to make N2O3.
“Another possibility is that nitrite binds to MetHb which subsequently reacts with NO to make N2O3 [47].”
From Mechanisms of nitrite bioactivation (2014) · cites this paper as [47]
Formation of N2O3 from nitrite would facilitate export of NO activity from the red blood cell and evidence for the formation of this species has been reported.
“Formation of N2O3 from nitrite would facilitate export of NO activity from the red blood cell and evidence for the formation of this species has been reported [45–47, 99].”
From Mechanisms of nitrite bioactivation (2014) · cites this paper as [47]
Recent evidence points to dinitrogen trioxide (N2O3) as a plausible intermediate for generation of NO downstream from nitrite reduction.
“Recent evidence points towards the formation of the nitrosating agent dinitrogen trioxide (N2O3) as one such plausible intermediate for the generation of NO downstream from nitrite reduction (Scheme 2) [42-45].”
From Current perspectives and challenges in understanding the role of nitrite as an integral player in nitric oxide biology and therapy (2011) · cites this paper as [43]
Exogenous administration of nitrite correlates with increased levels of S-nitrosothiols in red blood cells and other tissues both in vivo and in vitro.
“exogenous administration of nitrite correlates with increased levels of S-nitrosothiols in red blood cells and other tissues both in vivo and in vitro [25, 43, 46-53].”
From Current perspectives and challenges in understanding the role of nitrite as an integral player in nitric oxide biology and therapy (2011) · cites this paper as [43]
Nitrite supplementation to intact organisms is associated with a widespread increase in the concentration of nitrite and production of NO-derived species such as S-nitrosothiols or nitrosylhemes in several tissues.
“Many reports show that nitrite supplementation to intact organisms is associated with a widespread increase in the concentration of this anion and production of NO-derived species such as S-nitrosothiols or nitrosylhemes in several tissues[25, 43, 46, 48, 49, 96].”
From Current perspectives and challenges in understanding the role of nitrite as an integral player in nitric oxide biology and therapy (2011) · cites this paper as [43]
A potential mechanism by which nitrite could induce cGMP-independent effects is S-nitrosation of cysteine residues, a potential nitrite-induced post-translational modification that can alter protein function.
“A potential mechanism by which nitrite could induce cGMP-independent effects is S-nitrosation of cysteine residues, which is being increasingly recognized as a potential nitrite-induced post-translational modification that can alter protein function[17, 43, 46, 47, 51, 96].”
From Current perspectives and challenges in understanding the role of nitrite as an integral player in nitric oxide biology and therapy (2011) · cites this paper as [43]
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- Authors
- Basu, S., Grubina, R., Huang, J., Conradie, J., Huang, Z., Jeffers, A., Jiang, A., He, X., Azarov, I., Seibert, R., Mehta, A., Patel, R., King, S. B., Hogg, N., Ghosh, A., Gladwin, M. T., & Kim-Shapiro, D. B.
- Affiliations
- Wake Forest University (US)
- National Institutes of Health (US)
- University of the Free State (ZA)
- Virginia Tech - Wake Forest University School of Biomedical Engineering & Sciences (US)
- University of Alabama (US)
- Medical College of Wisconsin (US)
- UiT The Arctic University of Norway (NO)
- Corresponding author
- Gladwin, Mark T
- ORCID
- Venue
- Nature Chemical Biology
- Published
- 2007-11-04
- Volume
- 3
- Issue
- 12
- Pages
- 785-794
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- OpenAlex
- W1969488383
- Cited by
- 224
- References
- 50
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 5 · 2023: 5 · 2022: 3 · 2021: 10 · 2020: 4 · 2019: 3 · 2018: 9 · 2017: 9 · 2016: 9 · 2015: 10 · 2014: 18 · 2013: 18 · 2012: 19
- FWCI
- 9.92
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Chemical Biology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Heart, Lung, and Blood Institute (HL-62198, K02HL078706, R37HL058091, HL58091, R01HL062198)
- National Institute of General Medical Sciences (GM55792)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hemoglobin structure and function
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Physical Sciences › Chemistry › Inorganic Chemistry › Metal-Catalyzed Oxygenation Mechanisms
- Keywords
- dinitrogen trioxide, nitrite, hemoglobin, methemoglobin, nitric oxide, nitrite reductase, S-nitrosothiols, erythrocytes
- MeSH terms
- Catalysis, Electron Spin Resonance Spectroscopy, Hemoglobins, Iron, Models, Molecular, Molecular Conformation, Nitrite Reductases, Nitrites, Nitrogen Oxides, Oxidation-Reduction, Oxygen
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