Dinitrosyliron complexes and the mechanism(s) of cellular protein nitrosothiol formation from nitric oxide
Open accessAbstract
Nitrosothiols (RSNO), formed from thiols and metabolites of nitric oxide (•NO), have been implicated in a diverse set of physiological and pathophysiological processes, although the exact mechanisms by which they are formed biologically are unknown. Several candidate nitrosative pathways involve the reaction of •NO with O 2 , reactive oxygen species (ROS), and transition metals. We developed a strategy using extracellular ferrocyanide to determine that under our conditions intracellular protein RSNO formation occurs from reaction of •NO inside the cell, as opposed to cellular entry of nitrosative reactants from the extracellular compartment. Using this method we found that in RAW 264.7 cells RSNO formation occurs only at very low (<8 μM) O 2 concentrations and exhibits zero-order dependence on •NO concentration. Indeed, RSNO formation is not inhibited even at O 2 levels <1 μM. Additionally, chelation of intracellular chelatable iron pool (CIP) reduces RSNO formation by >50%. One possible metal-dependent, O 2 -independent nitrosative pathway is the reaction of thiols with dinitrosyliron complexes (DNIC), which are formed in cells from the reaction of •NO with the CIP. Under our conditions, DNIC formation, like RSNO formation, is inhibited by ≈50% after chelation of labile iron. Both DNIC and RSNO are also increased during overproduction of ROS by the redox cycler 5,8-dimethoxy-1,4-naphthoquinone. Taken together, these data strongly suggest that cellular RSNO are formed from free •NO via transnitrosation from DNIC derived from the CIP. We have examined in detail the kinetics and mechanism of RSNO formation inside cells.
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Recent evidence implicates cellular non-heme metal nitrosyls as important contributors to nitrosation reactions.
“The relative contributions of these mechanisms to biological nitrosation are not clear; however, recent evidence seems to implicate cellular non-heme metal nitrosyls as important contributors to nitrosation reactions (63).”
From What Part of NO Don't You Understand? Some Answers to the Cardinal Questions in Nitric Oxide Biology (2010) · cites this paper as [63]
A cardioprotective mitochondrially targeted S-nitrosothiol was shown recently to enhance oxygen levels under hypoxic conditions and to promote S-nitrosation of mitochondrial protein thiols.
“Indeed, a cardioprotective mitochondrially targeted S-nitrosothiol was shown recently to enhance oxygen levels under hypoxic conditions and to promote S-nitrosation of mitochondrial protein thiols (63).”
From What Part of NO Don't You Understand? Some Answers to the Cardinal Questions in Nitric Oxide Biology (2010) · cites this paper as [63]
DNICs are formed in the vasculature from nitrosothiols and are in equilibrium with the nitrosothiol pool.
“It was proposed that DNICs are formed in the vasculature from nitrosothiols and that they are in equilibrium with the nitrosothiol pool [103,104].”
From On the chemical biology of the nitrite/sulfide interaction (2015) · cites this paper as [104]
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- Authors
- Bosworth, C. A., Toledo, J. C., Zmijewski, J. W., Li, Q., & Lancaster, J. R.
- Affiliations
- University of Alabama (US)
- Universidade Federal do ABC (BR)
- Medicine,
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2009-03-24
- Volume
- 106
- Issue
- 12
- Pages
- 4671-4676
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2660757
- OpenAlex
- W2013547325
- Cited by
- 220
- References
- 3
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 9 · 2023: 9 · 2022: 7 · 2021: 16 · 2020: 9 · 2019: 13 · 2018: 13 · 2017: 9 · 2016: 14 · 2015: 10 · 2014: 19 · 2013: 19 · 2012: 21
- FWCI
- 14.85
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (HL 074391, R01HL071189, HL 71189, R01HL074391)
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hemoglobin structure and function
- Keywords
- S-nitrosothiols, nitric oxide, transnitrosation, protein nitrosylation, intracellular iron, ferrocyanide, reactive oxygen species, RAW 264.7 macrophages, redox cycling, oxygen dependence
- MeSH terms
- Animals, Cell Line, Extracellular Space, Iron, Iron Chelating Agents, Macrophages, Nitric Oxide, Nitrogen Oxides, Oxidation-Reduction, Oxygen, Proteins, Time Factors, Cell Hypoxia, Reactive Oxygen Species, Oxidative Stress, S-Nitrosothiols, Intracellular Space, Mice
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