The Reaction between Nitrite and Deoxyhemoglobin
Open accessAbstract
Recent evidence suggests that the reaction between nitrite and deoxygenated hemoglobin provides a mechanism by which nitric oxide is synthesized in vivo. This reaction has been previously defined to follow second order kinetics, although variable product stoichiometry has been reported. In this study we have re-examined this reaction and found that under fully deoxygenated conditions the product stoichiometry is 1:1 (methemoglobin:nitrosylhemoglobin), and unexpectedly, the kinetics deviate substantially from a simple second order reaction and exhibit a sigmoidal profile. The kinetics of this reaction are consistent with an increase in reaction rate elicited by heme oxidation and iron-nitrosylation. In addition, conditions that favor the "R" conformation show an increased rate over conditions that favor the "T" conformation. The reactivity of nitrite with heme is clearly more complex than has been previously realized and is dependent upon the conformational state of the hemoglobin tetramer, suggesting that the nitrite reductase activity of hemoglobin is under allosteric control.
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The reaction of two deoxyHb molecules with nitrite yields one nitrosyl Hb and one methemoglobin, with pH critically influencing the process.
“The studies by Huang et al. (445) confirmed the overall stoichiometry of two molecules of deoxyHb generating one molecule of nitrosyl Hb and one molecule of methemoglobin (Eq. 7), consistent with electron transfer from a ferrous Hb to nitrite and indicated the critical influence of pH in the process.”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [445]
The rate of nitrite reduction by Hb depends on the allosteric state of the protein, with vacant hemes in an R-state Hb tetramer reacting about 100 times faster than those in the T-state.
“Interestingly, the rate of reduction has been found to depend on the allosteric state of the protein, with vacant hemes in an R-state Hb tetramer reacting about 100 times faster than those in the T-state [36–38].”
From Mechanisms of nitrite bioactivation (2014) · cites this paper as [37]
The reduction of nitrite by Hb occurs as NO2− + HbFe2+ + H+ → NO + HbFe3+ + OH−.
“(1)NO2−+HbFe2++H+→NO+HbFe3++OH−”
From Mechanisms of nitrite bioactivation (2014) · cites this paper as [37]
Intra-arterial infusion of nitrite at near-physiological levels causes vasodilation in an arterio-venous gradient manner that is influenced by R-T state conversion and oxygen tension implicating red cell reduction of nitrite to NO.
“However, experiments by Cosby et al showed that intra-arterial infusion of nitrite at near-physiological levels causes vasodilation in an arterio-venous gradient manner that is influenced by R-T state conversion and oxygen tension implicating red cell reduction of nitrite to NO [19, 106, 107].”
From Inorganic nitrite therapy: historical perspective and future directions (2011) · cites this paper as [106]
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References 54 · Cited by 253
Research works printed but not linked: 4
- Brooks, J. (1937) Proc. R. Soc. Lond. Ser. B Biol. Sci. 123, 368 -382
- Antonini, E., and Brunori, M. (1971) Hemoglobin and Myoglobin in Their Reactions with Ligands, pp. 1-11 North Holland Publishing Company, Amsterdam
- Xu, X., Cho, M., Spencer, N. Y., Patel, N., Huang, Z., Shields, H., King, S. B., Gladwin, M. T., Hogg, N., and Kim-Shapiro, D. B. (2003) Proc. Natl. Acad. Sci. U. S. A. 100, 11303-11308
- Williams, P. A., Fulop, V., Garman, E. F., Saunders, N. F. W., Ferguson, S. J., and Hajdu, J. (1997) Nature 389, 406 -412
- Authors
- Huang, K. T., Keszler, A., Patel, N., Patel, R. P., Gladwin, M. T., Kim-Shapiro, D. B., & Hogg, N.
- Affiliations
- Wake Forest University Health Sciences (US)
- Medical College of Wisconsin (US)
- University of Alabama at Birmingham (US)
- National Institutes of Health (US)
- Corresponding author
- Hogg, Neil
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2005-09
- Volume
- 280
- Issue
- 35
- Pages
- 31126-31131
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2072307990
- Cited by
- 253
- References
- 54
- Citations by year
- 2026: 3 · 2025: 1 · 2024: 4 · 2023: 1 · 2022: 5 · 2021: 1 · 2020: 5 · 2019: 5 · 2018: 12 · 2017: 6 · 2016: 10 · 2015: 14 · 2014: 17 · 2013: 21 · 2012: 17
- FWCI
- 10.30
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- North Carolina Biotechnology Center
- National Institutes of Health (EB-001980, GM55792, HL58091)
- National Heart, Lung, and Blood Institute (R01HL070146, R01HL70146, HL58091, R01HL058091)
- National Institute of General Medical Sciences (T32GM008361, T32 GM 08361, GM55792)
- National Institute of Biomedical Imaging and Bioengineering (EB001980, P41EB001980)
- NIH Clinical Center
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hemoglobin structure and function
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heme Oxygenase-1 and Carbon Monoxide
- Keywords
- nitrite, deoxyhemoglobin, nitric oxide production, methemoglobin, nitrosylhemoglobin, reaction kinetics, sigmoidal kinetics, heme oxidation, allosteric regulation, nitrite reductase activity
- MeSH terms
- Allosteric Regulation, Electron Spin Resonance Spectroscopy, Hemoglobins, Humans, Models, Biological, Nitrites, Oxidation-Reduction, Oxygen, Protein Conformation
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