The DOI matches its Crossref record; 50 of the 50 references it cites were found in a registry or an index.
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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In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
Citations
Cites
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Nitrite reduction to nitric oxide by deoxyhemoglobin vasodilates the human circulation
Cosby, K., Partovi, K. S., Crawford, J. H., Patel, R. P., Reiter, C. D., Martyr, S., Yang, B. K., Waclawiw, M. A., Zalos, G., Xu, X., et al. (2003) · Nature Medicine · doi:10.1038/nm954 · Cited by 1,807
Self-citationPrinciples of structure, bonding, and reactivity for metal nitrosyl complexes
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Oxidation of nitrogen-oxides by bound dioxygen in hemoproteins
Doyle, M. P., & Hoekstra, J. W. (1981) · Journal of Inorganic Biochemistry · doi:10.1016/s0162-0134(00)80291-3 · Cited by 643
Mechanism of NO-induced oxidation of myoglobin and hemoglobin
Eich, R. F., Li, T., Lemon, D. D., Doherty, D. H., Curry, S. R., Aitken, J. F., Mathews, A. J., Johnson, K. A., Smith, R. D., Phillips, et al. (1996) · Biochemistry · doi:10.1021/bi960442g · Cited by 613
The emerging biology of the nitrite anion
Gladwin, M. T., Schechter, A. N., Kim-Shapiro, D. B., Patel, R. P., Hogg, N., Shiva, S., Cannon, R. O., Kelm, M., Wink, D. A., Espey, M. G., et al. (2005) · Nature Chemical Biology · doi:10.1038/nchembio1105-308 · Cited by 609
Self-citationShiva, S., Huang, Z., Grubina, R., Sun, J., Ringwood, L. A., MacArthur, P. H., Xu, X., Murphy, E., Darley-Usmar, V. M., & Gladwin, M. T. (2007) · Circulation Research · doi:10.1161/01.res.0000260171.52224.6b · Cited by 599
Self-citationLauer, T., Preik, M., Rassaf, T., Strauer, B. E., Deussen, A., Feelisch, M., & Kelm, M. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.221381098 · Cited by 585
Enzymatic function of hemoglobin as a nitrite reductase that produces NO under allosteric control
Huang, Z. (2005) · Journal of Clinical Investigation · doi:10.1172/jci24650 · Cited by 520
Self-citation
Research works printed but not linked: 1
- Williams, D.L.H. Nitrosation Reactions and the Chemsitry of Nitric Oxide 5–8 (Elsevier, Amsterdam, 2004).
Cited by
Sorted by citations
The nitrate-nitrite-nitric oxide pathway in physiology and therapeutics
Lundberg, J. O., Weitzberg, E., & Gladwin, M. T. (2008) · Nature Reviews Drug Discovery · doi:10.1038/nrd2466 · Cited by 2,739
Self-citationNitrate and nitrite in biology, nutrition and therapeutics
Lundberg, J. O., Gladwin, M. T., Ahluwalia, A., Benjamin, N., Bryan, N. S., Butler, A., Cabrales, P., Fago, A., Feelisch, M., Ford, P. C., et al. (2009) · Nature Chemical Biology · doi:10.1038/nchembio.260 · Cited by 617
Self-citationSources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation
Tejero, J., Shiva, S., & Gladwin, M. T. (2019) · Physiological Reviews · doi:10.1152/physrev.00036.2017 · Cited by 541
Self-citationNitrite as Regulator of Hypoxic Signaling in Mammalian Physiology
van Faassen, E. E., Bahrami, S., Feelisch, M., Hogg, N., Kelm, M., Kim‐Shapiro, D. B., Kozlov, A. V., Li, H., Lundberg, J. O., Mason, R., et al. (2009) · Medicinal Research Reviews · doi:10.1002/med.20151 · Cited by 435
Self-citationMaia, L. B., & Moura, J. J. G. (2014) · Chemical Reviews · doi:10.1021/cr400518y · Cited by 401
Metadata
- 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 › Biochemistry › Hemoglobin structure and function
- Health Sciences › Medicine › Physiology (medical) › 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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