The new chemical biology of nitrite reactions with hemoglobin: R-state catalysis, oxidative denitrosylation, and nitrite reductase/anhydrase
Abstract
Because of their critical biological roles, hemoglobin and myoglobin are among the most extensively studied proteins in human history, while nitrite tops the list of most-studied small molecules. And although the reactions between them have been examined for more than 140 years, a series of unusual and critical allosterically modulated reactions have only recently been characterized. In this Account, we review three novel metal- and nitrite-catalyzed reaction pathways in the context of historical studies of nitrite and hemoglobin chemistry and attempt to place them in the biological framework of hypoxic signaling. Haldane first described the reaction between nitrite and deoxymyoglobin, forming iron-nitrosylated myoglobin, in his analysis of the meat-curing process more than a century ago. The reaction of nitrous acid with deoxyhemoglobin to form nitric oxide (NO) and methemoglobin was more fully characterized by Brooks in 1937, while the mechanism and unusual behavior of this reaction were further detailed by Doyle and colleagues in 1981. During the past decade, multiple physiological studies have surprisingly revealed that nitrite represents a biological reservoir of NO that can regulate hypoxic vasodilation, cellular respiration, and signaling. Importantly, chemical analysis of this new biology suggests a vital role for deoxyhemoglobin- and deoxymyoglobin-dependent nitrite reduction in these processes. The use of UV-vis deconvolution and electron paramagnetic resonance (EPR) spectroscopy, in addition to refined gas-phase chemiluminescent NO detection, has led to the discovery of three novel and unexpected chemistries between nitrite and deoxyhemoglobin that may contribute to and facilitate hypoxic NO generation and signaling. First, R-state, or allosteric, autocatalysis of nitrite reduction increases the rate of NO generation by deoxyhemoglobin and results in maximal NO production at approximately 50% hemoglobin oxygen saturation, which is physiologically associated with greatest NO-dependent vasodilation. Second, oxidative denitrosylation of the iron-nitrosyl product formed in the deoxyhemoglobin-nitrite reaction allows for NO formation and release in a partially oxygenated environment. Finally, the deoxyhemoglobin-nitrite reaction participates in a nitrite reductase/anhydrase redox cycle that catalyzes the anaerobic conversion of two molecules of nitrite into dinitrogen trioxide (N(2)O(3)). N(2)O(3) may then nitrosate proteins, diffuse across hydrophobic erythrocyte membrane channels such as aquaphorin or Rh, or reconstitute NO via homolysis to NO and NO(2)(*). Importantly, the nitrite reductase/anhydrase redox pathway also represents a novel mechanism of both anaerobic and metal-catalyzed N(2)O(3) formation and S-nitrosation and may thus play a vital role in NO-dependent signaling in a hypoxic and heme-rich environment. We consider how these reactions may contribute to physiological and pathological hypoxic signaling.
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Formation of N2O3 under physiological conditions might require special spatial localization conditions in the red blood cell.
“formation of N2O3 under physiological conditions might require special spatial localization conditions in the red blood cell [14].”
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 [14]
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- Authors
- Gladwin, M. T., Grubina, R., & Doyle, M. P.
- Affiliations
- National Institutes of Health (US)
- University of Maryland, College Park (US)
- Corresponding author
- Gladwin, Mark T.
- Venue
- Accounts of Chemical Research
- Publisher
- American Chemical Society (ACS)
- Published
- 2008-09-11
- Volume
- 42
- Issue
- 1
- Pages
- 157-167
- ISSN
- 0001-4842 (ISSN-L)
- 1520-4898
- OpenAlex
- W1977243529
- Cited by
- 194
- References
- 54
- Citations by year
- 2026: 4 · 2025: 10 · 2024: 6 · 2023: 4 · 2022: 6 · 2021: 9 · 2020: 5 · 2019: 5 · 2018: 11 · 2017: 11 · 2016: 16 · 2015: 8 · 2014: 13 · 2013: 23 · 2012: 13
- FWCI
- 7.29
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Accounts of Chemical Research (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hemoglobin structure and function
- Physical Sciences › Chemistry › Inorganic Chemistry › Metal-Catalyzed Oxygenation Mechanisms
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Keywords
- nitrite, hemoglobin, myoglobin, dinitrogen trioxide, nitric oxide production, hypoxia signaling, methemoglobin, iron nitrosyl complexes, hypoxic vasodilation
- MeSH terms
- Allosteric Regulation, Catalysis, Hemoglobins, Humans, Methemoglobin, Nitrite Reductases, Nitrites, Oxidation-Reduction, Oxygen, Protein Conformation, Reactive Nitrogen Species
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