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Human Neuroglobin Functions as a Redox-regulated Nitrite Reductase
Open accessAbstract
Neuroglobin is a highly conserved hemoprotein of uncertain physiological function that evolved from a common ancestor to hemoglobin and myoglobin. It possesses a six-coordinate heme geometry with proximal and distal histidines directly bound to the heme iron, although coordination of the sixth ligand is reversible. We show that deoxygenated human neuroglobin reacts with nitrite to form nitric oxide (NO). This reaction is regulated by redox-sensitive surface thiols, cysteine 55 and 46, which regulate the fraction of the five-coordinated heme, nitrite binding, and NO formation. Replacement of the distal histidine by leucine or glutamine leads to a stable five-coordinated geometry; these neuroglobin mutants reduce nitrite to NO ∼2000 times faster than the wild type, whereas mutation of either Cys-55 or Cys-46 to alanine stabilizes the six-coordinate structure and slows the reaction. Using lentivirus expression systems, we show that the nitrite reductase activity of neuroglobin inhibits cellular respiration via NO binding to cytochrome c oxidase and confirm that the six-to-five-coordinate status of neuroglobin regulates intracellular hypoxic NO-signaling pathways. These studies suggest that neuroglobin may function as a physiological oxidative stress sensor and a post-translationally redox-regulated nitrite reductase that generates NO under six-to-five-coordinate heme pocket control. We hypothesize that the six-coordinate heme globin superfamily may subserve a function as primordial hypoxic and redox-regulated NO-signaling proteins. Neuroglobin is a highly conserved hemoprotein of uncertain physiological function that evolved from a common ancestor to hemoglobin and myoglobin. It possesses a six-coordinate heme geometry with proximal and distal histidines directly bound to the heme iron, although coordination of the sixth ligand is reversible. We show that deoxygenated human neuroglobin reacts with nitrite to form nitric oxide (NO). This reaction is regulated by redox-sensitive surface thiols, cysteine 55 and 46, which regulate the fraction of the five-coordinated heme, nitrite binding, and NO formation. Replacement of the distal histidine by leucine or glutamine leads to a stable five-coordinated geometry; these neuroglobin mutants reduce nitrite to NO ∼2000 times faster than the wild type, whereas mutation of either Cys-55 or Cys-46 to alanine stabilizes the six-coordinate structure and slows the reaction. Using lentivirus expression systems, we show that the nitrite reductase activity of neuroglobin inhibits cellular respiration via NO binding to cytochrome c oxidase and confirm that the six-to-five-coordinate status of neuroglobin regulates intracellular hypoxic NO-signaling pathways. These studies suggest that neuroglobin may function as a physiological oxidative stress sensor and a post-translationally redox-regulated nitrite reductase that generates NO under six-to-five-coordinate heme pocket control. We hypothesize that the six-coordinate heme globin superfamily may subserve a function as primordial hypoxic and redox-regulated NO-signaling proteins.
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In the citing paper
“With reported values of being about 3000 for KHis [59], the binding of the iron plays a major role in limiting the rate of nitrite reduction by Ngb, giving an overall bimolecular rate constant of about 0.1 M−1s−1 at neutral pH [58].”
From Mechanisms of nitrite bioactivation (2014) · cites this paper as [58]
In the citing paper
“The basic mechanism of reduction of nitrite to NO by Neuroglobin (Ngb) is also similar to that of Mb and Hb (Equation 1), except that it is complicated by the fact that the heme iron of Ngb is predominately hexacoordinate [58].”
From Mechanisms of nitrite bioactivation (2014) · cites this paper as [58]
In the citing paper
“Interestingly, the affinity of the heme iron for the distal histidine can be increased through protein modification, thereby increasing the rate of nitrite reduction [58, 60].”
From Mechanisms of nitrite bioactivation (2014) · cites this paper as [58]
In the citing paper
“Formation of a disulfide bond between cysteines 46 and 55 the pentacoordinate Ngb form [58].”
From Mechanisms of nitrite bioactivation (2014) · cites this paper as [58]
In the citing paper
“the nitrite reductase activity of neuroglobin [63, 64, 70, 76] or cytochrome c [47] is negligible when the heme is hexacoordinated.”
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 [64]
In the citing paper
“Nitrite reduction is not exclusive to hemoglobin and myoglobin, with a variety of heme-containing and non-heme containing proteins including xanthine oxidoreductase [21, 22], aldehyde oxidase [62], neuroglobin [63, 64], eNOS [65], cytochrome c [47], carbonic anhydrase [66], cytochrome c oxidase [67], complex III [68], and cytochrome P450 [69] being suggested as mediators of NO-formation.”
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 [64]
In the citing paper
“neuroglobin will increase its penta-coordinated character upon oxidation of Cys46 and Cys55 to form a disulfide bond [64, 80-82].”
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 [64]
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Metadata
- Authors
- Tiso, M., Tejero, J., Basu, S., Azarov, I., Wang, X., Simplaceanu, V., Frizzell, S., Jayaraman, T., Geary, L., Shapiro, C., Ho, C., Shiva, S., Kim-Shapiro, D. B., & Gladwin, M. T.
- Affiliations
- University of Pittsburgh (US)
- Wake Forest University (US)
- National Institutes of Health (US)
- Carnegie Mellon University (US)
- Corresponding author
- Gladwin, Mark T.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2011-05
- Volume
- 286
- Issue
- 20
- Pages
- 18277-18289
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC3093900
- OpenAlex
- W2086187832
- Cited by
- 287
- References
- 57
- Citations by year
- 2026: 9 · 2025: 14 · 2024: 8 · 2023: 12 · 2022: 16 · 2021: 13 · 2020: 16 · 2019: 16 · 2018: 20 · 2017: 22 · 2016: 22 · 2015: 20 · 2014: 27 · 2013: 30 · 2012: 31
- FWCI
- 15.04
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Heart Association
- Rice University
- National Institutes of Health (HL058091, HL098032)
- National Heart, Lung, and Blood Institute (R29HL058091, HL058091, HL098032, R37HL058091, R01HL058091, R01HL098032)
- National Institute of General Medical Sciences (R01GM084614, GM-084614)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Hemoglobin structure and function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heme Oxygenase-1 and Carbon Monoxide
- Physical Sciences › Chemistry › Inorganic Chemistry › Metal-Catalyzed Oxygenation Mechanisms
- Keywords
- neuroglobin, nitrite reductase, nitric oxide production, heme coordination, five-coordinate heme, distal histidine, redox regulation, hypoxia signaling, oxidative stress sensing, cytochrome c oxidase inhibition, cellular respiration
- MeSH terms
- Neuroglobin, Animals, Globins, Humans, Male, Nerve Tissue Proteins, Nitric Oxide, Nitrite Reductases, Nitrites, Oxidation-Reduction, Oxygen Consumption, Rats, Sprague-Dawley, Oxidative Stress, Amino Acid Substitution, Mutation, Missense, Rats
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