The functional nitrite reductase activity of the heme-globins
Open accessAbstract
Hemoglobin and myoglobin are among the most extensively studied proteins, and nitrite is one of the most studied small molecules. Recently, multiple physiologic studies have surprisingly revealed that nitrite represents a biologic reservoir of NO that can regulate hypoxic vasodilation, cellular respiration, and signaling. These studies suggest a vital role for deoxyhemoglobin- and deoxymyoglobin-dependent nitrite reduction. Biophysical and chemical analysis of the nitrite-deoxyhemoglobin reaction has revealed unexpected chemistries between nitrite and deoxyhemoglobin that may contribute to and facilitate hypoxic NO generation and signaling. The first is that hemoglobin is an allosterically regulated nitrite reductase, such that oxygen binding increases the rate of nitrite conversion to NO, a process termed R-state catalysis. The second chemical property is oxidative denitrosylation, a process by which the NO formed in the deoxyhemoglobin-nitrite reaction that binds to other deoxyhemes can be released due to heme oxidation, releasing free NO. Third, the reaction undergoes a nitrite reductase/anhydrase redox cycle that catalyzes the anaerobic conversion of 2 molecules of nitrite into dinitrogen trioxide (N2O3), an uncharged molecule that may be exported from the erythrocyte. We will review these reactions in the biologic framework of hypoxic signaling in blood and the heart.
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Nitrite appears to mediate the majority of its effects through bioactivation to NO, mainly via nitrite reductases that have selective activity under oxygen/hypoxic/ischaemic conditions.
“Nitrite appears to mediate the majority of its effects through bioactivation to NO.This occurs mainly via nitrite reductases, which have selective activity under oxygen/hypoxic/ischaemic conditions”
From Vascular effects of dietary nitrate (as found in green leafy vegetables and beetroot) via the nitrate-nitrite-nitric oxide pathway (2013) · cites this paper as [121]
The section on myoglobin as a nitrite reductase describes nitrite reduction to NO at different oxygen tensions and reports that myoglobin accounts for more than 70% of the effects examined in cardiac tissue. The section on hypoxic vasodilation also links nitrite-to-NO conversion to hypoxia. These passages support the proposed pathway under low-oxygen and ischemic conditions, but do not establish that it mediates the majority of nitrite’s effects generally. (LLM, conf=0.84)
Experimental — accuracy not yet measuredRed blood cells contribute to NO bioactivity by reducing nitrite to NO under hypoxic conditions.
“Red blood cells contribute to NO bioactivity by reducing nitrite to NO under hypoxic conditions [258,259].”
From Dietary Nitrate-Rich Vegetables as Natural Modulators of Health: Mechanisms and Benefits in Ageing Populations (2026) · cites this paper as [259]
Nitrite reduction by heme proteins can mediate hypoxic vasodilation and other physiological responses.
“For instance, nitrite reduction by heme proteins can mediate hypoxic vasodilation and other physiological responses”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [367]
Oxygen levels can impact the oxidation/reduction properties of different proteins and regulate NO levels.
“In this context, it has become increasingly appreciated that oxygen levels can impact the oxidation/reduction properties of different proteins and regulate NO levels”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [367]
Mathematical modeling of the reaction of Hb with nitrite at different oxygen tensions yields a bell-shaped dependence of observed rates versus oxygen concentration, with maximal NO generation around 50% Hb oxygen saturation, consistent with experimental data.
“In fact, the reaction of Hb with nitrite has been modeled mathematically at different oxygen tensions. The combination of a faster rate at higher oxygen, but increased availability of deoxyHb at low oxygen, leads to bell-shaped dependence of the observed rates versus the oxygen concentration with the maximal rates of NO generation around 50% Hb oxygen saturation, consistent with experimental data”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [367]
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 [367]
Nitrite metabolism can be activated by hypoxia, low pH and reactions with metalloproteins.
“Nitrite metabolism can be activated by hypoxia, low pH and reactions with metalloproteins[50–58].”
From Enterosalivary nitrate metabolism and the microbiome: Intersection of microbial metabolism, nitric oxide and diet in cardiac and pulmonary vascular health (2017) · cites this paper as [56]
The rate of NO production from Hb-mediated nitrite reduction is maximal at partial oxygen saturations near the p50 of Hb.
“The rate of NO production is thus maximal at partial oxygen saturations near the p50 of Hb (Figure 3) [36, 38].”
From Mechanisms of nitrite bioactivation (2014) · cites this paper as [38]
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 [38]
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References 136 · Cited by 293
Research works printed but not linked: 7
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- Authors
- Gladwin, M. T., & Kim-Shapiro, D. B.
- Affiliations
- National Institutes of Health (US)
- Department of Physics, Wake Forest University, Winston-Salem, NC
- Corresponding author
- Gladwin, Mark T.
- ORCID
- Gladwin, Mark T.
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2008-10-01
- Volume
- 112
- Issue
- 7
- Pages
- 2636-2647
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- PMC
- PMC2556603
- OpenAlex
- W2030984782
- Cited by
- 293
- References
- 136
- Citations by year
- 2026: 11 · 2025: 12 · 2024: 8 · 2023: 19 · 2022: 13 · 2021: 10 · 2020: 10 · 2019: 12 · 2018: 11 · 2017: 20 · 2016: 21 · 2015: 12 · 2014: 22 · 2013: 31 · 2012: 20
- FWCI
- 1.61
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Blood (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (HL058091)
- National Heart, Lung, and Blood Institute (R29HL058091, HL058091, K02HL078706, R37HL058091, HL078706, R01HL058091)
- NHLBI Division of Intramural Research
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hemoglobin structure and function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heme Oxygenase-1 and Carbon Monoxide
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Keywords
- nitrite reductase, hemoglobin, myoglobin, nitric oxide, hypoxic vasodilation, allosteric regulation, heme oxidation, dinitrogen trioxide, hypoxia signaling, erythrocytes, heart
- MeSH terms
- Allosteric Regulation, Animals, Erythrocytes, Hemoglobins, Humans, Nitric Oxide, Nitrite Reductases, Nitrites
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