Enzymatic function of hemoglobin as a nitrite reductase that produces NO under allosteric control
Open accessAbstract
Hypoxic vasodilation is a fundamental, highly conserved physiological response that requires oxygen and/or pH sensing coupled to vasodilation. While this process was first characterized more than 80 years ago, the precise identity and mechanism of the oxygen sensor and mediators of vasodilation remain uncertain. In support of a possible role for hemoglobin (Hb) as a sensor and effector of hypoxic vasodilation, here we show biochemical evidence that Hb exhibits enzymatic behavior as a nitrite reductase, with maximal NO generation rates occurring near the oxy-to-deoxy (R-to-T) allosteric structural transition of the protein. The observed rate of nitrite reduction by Hb deviates from second-order kinetics, and sigmoidal reaction progress is determined by a balance between 2 opposing chemistries of the heme in the R (oxygenated conformation) and T (deoxygenated conformation) allosteric quaternary structures of the Hb tetramer--the greater reductive potential of deoxyheme in the R state tetramer and the number of unligated deoxyheme sites necessary for nitrite binding, which are more plentiful in the T state tetramer. These opposing chemistries result in a maximal nitrite reduction rate when Hb is 40-60% saturated with oxygen (near the Hb P50), an apparent ideal set point for hypoxia-responsive NO generation. These data suggest that the oxygen sensor for hypoxic vasodilation is determined by Hb oxygen saturation and quaternary structure and that the nitrite reductase activity of Hb generates NO gas under allosteric and pH control.
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Nitrite bioactivation is most prevalent during rapid deoxygenation, reaching a maximum conversion and nitric oxide-mediated effects at 50% oxygen bound hemoglobin.
“They showed that nitrite bioactivation is most prevalent during rapid deoxygenation, reaching a maximum conversion and nitric oxide-mediated effects at 50% oxygen bound hemoglobin.73,74”
From Nitrate-Nitrite-Nitric Oxide Pathway: Implications for Anesthesiology and Intensive Care (2010) · cites this paper as [73]
The Figure 2 passage reports a maximal nitrite-reductase rate at 40–60% hemoglobin oxygen saturation, consistent with the claimed value of about 50%. The Physiological implications section links this reaction to NO generation and possible vasodilation, but it does not establish that bioactivation is greatest during *rapid* deoxygenation or that NO-mediated effects themselves reach a measured maximum at 50% saturation. (LLM, conf=0.86)
Experimental — accuracy not yet measuredNitrite 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 [120]
The Introduction links nitrite-associated vasodilation to its conversion to NO by deoxyhemoglobin, and the results report that hemoglobin’s nitrite-reductase rate varies with oxygen saturation. The paper does not establish that the majority of nitrite’s effects occur through NO bioactivation or that nitrite reductases are the main route across those effects; the Physiological implications section also discusses nonenzymatic reduction. Page numbers were not available in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThe reaction of deoxyHb with nitrite shows an increase in instantaneous rate as the reaction progresses due to a T-state to R-state shift; NO binds unreacted deoxyHb to stabilize the R-state (R-state autocatalysis).
“The reaction of deoxyHb with nitrite shows an increase in the instantaneous reaction rate as the reaction progresses (447). Studies with T-state and R-state Hb–stabilizing compounds have unambiguously identified the reason for this change is the shift from T-state to R-state during the course of the reaction, as the NO formed in the reaction binds to the unreacted deoxyHb to stabilize the R-state.”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [447]
Rate constants for the reaction of Hb with nitrite change from 0.12 M−1s−1 for T-state Hb to 6.0 M−1s−1 for R-state Hb.
“The rate constants for the reaction of Hb with nitrite change from 0.12 M−1s−1 for T-state Hb to 6.0 M−1s−1 for R-state Hb (Table 3) (447).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [447]
The scheme of heme protein-mediated nitrite reduction applies to virtually all heme proteins studied to date, including Hb, Mb, Ngb, Cygb, CBS, globin X, plant and cyanobacterial Hb, flavohemoglobin, heme-albumin, cytochrome c, protoglobin, and microperoxidase-11.
“This scheme has been found to apply to virtually all the heme protein–mediated nitrite reduction reactions studied to date, including Hb (248, 447), Mb (247, 862), neuroglobin (Ngb) (932, 945), Cygb (182, 571, 780), cystathionine β-synthase (CBS) (149, 350), globin X (184), plant and cyanobacterial Hb (phytohemoglobins) (905, 946), flavohemoglobin (340), heme-albumin (43), cytochrome c (41), prot”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [447]
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 [53]
Inorganic nitrite demonstrates robust NO-signaling effects and contributes to basal vascular tone, blood pressure, protection from endothelial dysfunction and vascular inflammation under conditions of metabolic and inflammatory stress.
“As with NOS-derived NO, inorganic nitrite demonstrates robust NO-signaling effects[52,53,57,59] and contributes to basal vascular tone[51,55,60,61], blood pressure[62–66], protection from endothelial dysfunction[67–71] and vascular inflammation[72] under conditions of metabolic and inflammatory stress.”
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 [53]
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 [36]
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 [36]
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 [36]
Taking a bimolecular rate constant of 1 M−1s−1, 0.01 M heme, and 100 nM nitrite, the maximum rate of NO production at the p50 oxygen pressure would be 1 nanomolar/sec.
“The maximum rate of NO production at this oxygen pressure, taking a bimolecular rate constant of 1 M−1s−1 [36], 0.01 M heme, and 100 nM nitrite would be 1 nanomolar/sec.”
From Mechanisms of nitrite bioactivation (2014) · cites this paper as [36]
Differential reactivity of nitrite reduction versus oxidation controlled by oxygen tension underlies the model in which nitrite selectively produces NO during graded hypoxia.
“This differential reactivity of nitrite reduction versus oxidation being controlled by oxygen tension (i.e. presence of deoxygenated vs oxygenated hemoglobin / myoglobin) illustrates the biochemical mechanism underlying the proposed model in which nitrite can selectively produce NO during graded hypoxia [5, 25-28].”
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 [27]
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 [107]
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- Authors
- Huang, Z.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Huang, Z.
- ORCID
- Huang, Z.
- Venue
- Journal of Clinical Investigation
- Published
- 2005-08-01
- Volume
- 115
- Issue
- 8
- Pages
- 2099-2107
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC1177999
- OpenAlex
- W2120714892
- Cited by
- 520
- References
- 57
- Citations by year
- 2026: 7 · 2025: 6 · 2024: 16 · 2023: 18 · 2022: 9 · 2021: 11 · 2020: 17 · 2019: 19 · 2018: 21 · 2017: 20 · 2016: 25 · 2015: 29 · 2014: 33 · 2013: 41 · 2012: 40
- FWCI
- 13.83
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- North Carolina Biotechnology Center
- National Institutes of Health (GM55792, HL58091)
- National Heart, Lung, and Blood Institute (R29HL058091, R37HL058091, HL58091, R01HL058091)
- National Institute of General Medical Sciences (R29GM055792, GM55792, R01GM055792)
- 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
- hemoglobin, nitrite reductase, nitric oxide production, hypoxic vasodilation, oxygen sensing, allosteric transition, pH control, oxygen saturation
- MeSH terms
- Allosteric Regulation, Allosteric Site, Animals, Hypoxia, Hemoglobins, Horses, Humans, Hydrogen-Ion Concentration, Kinetics, Nitric Oxide, Nitrite Reductases, Nitrites, Oxidation-Reduction, Vasodilation, Protein Structure, Tertiary
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