Nitroxidative, Nitrosative, and Nitrative Stress: Kinetic Predictions of Reactive Nitrogen Species Chemistry Under Biological Conditions
Abstract
A freely available Windows-based program, RNSim1A, is utilized to predict metal-independent reactive nitrogen species (RNS) chemistry (oxidation, nitrosation, and nitration) under simulated biological conditions and make the following specific predictions. (1) The peak in oxidative reactions that occurs in vitro with 1:1 fluxes of (*)NO and O(2)(*)(-) does not occur under biological conditions. (2) By far, the quantitatively dominant (92-99.6%) process in vivo is oxidation, compared to nitrosation and nitration. (3) Only five of the many possible RNS reactions involving thiol (glutathione, GSH) and tyrosine are quantitatively important biologically. (4) Under inflammatory conditions, approximately 1% of O(2)(*)(-) reacts with (*)NO to produce ONOO(-), with the remainder reacting with SOD. (5) The dominant reaction of tyrosyl radical is a radical swap with GSH, producing the glutathiyl radical and regenerating tyrosine. (6) Nitrosothiol is formed virtually exclusively via radical recombination (RS(*) + (*)NO) as opposed to reaction with nitrous anhydride (N(2)O(3)). (7) Nitrosothiol is an intermediate, not an endproduct, and responds dynamically to changes in the immediate chemical environment. (8) The formation of a nitroso group on a particular thiol can be considered a marker of increased reactivity of that thiol, and it is likely that other modifications of that thiol (oxidation, glutathiolation) are more abundant than nitrosation and may be the functionally significant modification. (9) Specific chemical mechanisms are proposed for posttranslational protein modification via nitrosation, nitration, glutathiolation, and also dithiol/disulfide exchange, with important roles for the thiolate anion and O(2) (suggesting possible mechanisms for O(2) sensing) and variable degrees of exposure of cysteine thiol and tyrosine phenolate. (10) Patterns of reactivity are similar for low (20 nM) and high (500 nM) steady-state levels of NO. (11) The dominant reactions are those involving reactants at the highest concentrations (CO(2), thiol, O(2)). Because of the dominance of oxidative processes caused by RNS, the term nitroxidative stress is proposed, emphasizing the oxidative (as opposed to nitrosative or nitrative) stress that dominates RNS actions under biological conditions.
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nNOS and iNOS can provide compensatory NO generation or exacerbated RNS synthesis.
“neuronal NOS (nNOS) and inducible NOS (iNOS) can provide compensatory NO generation or exacerbated RNS synthesis”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [547]
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- Authors
- Lancaster, J. R.
- Affiliations
- University of Alabama (US)
- Corresponding author
- Lancaster, Jack R.
- Venue
- Chemical Research in Toxicology
- Publisher
- American Chemical Society (ACS)
- Published
- 2006-08-18
- Volume
- 19
- Issue
- 9
- Pages
- 1160-1174
- ISSN
- 0893-228X (ISSN-L)
- 1520-5010
- OpenAlex
- W2084854699
- Cited by
- 219
- References
- 14
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 10 · 2023: 6 · 2022: 7 · 2021: 11 · 2020: 6 · 2019: 7 · 2018: 4 · 2017: 11 · 2016: 17 · 2015: 8 · 2014: 13 · 2013: 13 · 2012: 29
- FWCI
- 6.62
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Chemical Research in Toxicology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (HL 074391, R01HL071189, HL 71189, R01HL074391)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 46935, R01DK046935)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Keywords
- reactive nitrogen species, nitro-oxidative stress, nitrosative stress, nitrative stress, nitric oxide, superoxide, peroxynitrite, glutathione, tyrosine, nitrosation, nitration, S-nitrosothiols, radical recombination, post-translational modification, oxygen sensing, thiolate anion
- MeSH terms
- Kinetics, Models, Theoretical, Oxidation-Reduction, Reactive Nitrogen Species
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