Nitric Oxide and Reactive Species in Protein Modification

Nitric oxide (NO•) is a diatomic free radical that functions as a versatile biological messenger and, through rapid reactions with oxygen and superoxide, gives rise to a spectrum of reactive nitrogen species (RNS). These RNS—including peroxynitrite (ONOO−), nitrogen dioxide (NO₂•) and dinitrogen trioxide (N₂O₃)—can covalently modify amino acid side chains in proteins, most notably through nitration of tyrosine residues and S-nitrosylation of cysteines. Such post-translational modifications influence protein structure, activity and interactions in processes ranging from vascular tone regulation and immune defence to neurodegeneration and cancer. While reversible S-nitrosylation often serves as a regulatory switch in cell signalling, irreversible oxidation and nitration can compromise enzyme function, promote protein aggregation and trigger proteolysis. The transient nature and low abundance of many RNS challenge detection and quantification, spurring innovation in chemical probes, enrichment strategies and mass spectrometric analysis. A deeper understanding of RNS-mediated protein modification illuminates mechanisms of physiological regulation, pathological damage and offers new targets for therapeutic intervention.

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Nitric Oxide and Reactive Species in Protein Modification publication trend

The graph below shows the total number of articles in nitric oxide and reactive species in protein modification across all publications each year (not limited to Nature Index journals).

Technical terms

Nitric oxide (NO•): A small, diffusible free radical that modulates vascular tone, neurotransmission and immune responses.

Reactive nitrogen species (RNS): Molecules derived from NO• through reactions with oxygen or superoxide, capable of oxidising, nitrating or nitrosating biomolecules.

Peroxynitrite (ONOO−): A potent oxidant formed by the near-diffusion-limited reaction of NO• with superoxide (O₂•−), inducing protein oxidation and nitration.

Protein nitration: The covalent addition of a nitro (–NO₂) group to an aromatic residue, most commonly tyrosine, altering protein structure and function.

S-nitrosylation: The reversible attachment of an NO moiety to a cysteine thiol, serving as a regulatory post-translational modification in signalling pathways.

Nitrotyrosine: A stable marker of oxidative-nitrative stress formed when a nitro group is appended to the phenolic ring of tyrosine.

References

1. Nitroproteomics is instrumental for stratification and targeted treatments of astrocytoma patients: expert recommendations for advanced 3PM approach with improved individual outcomes. EPMA Journal (2023).
2. Phenyl Radical-Mediated Fluorogenic Cyclization for Specific Detection of Peroxynitrite. Analytical Chemistry (2025).
3. Exploration of Nitrotyrosine-Containing Proteins and Peptides by Antibody-Based Enrichment Strategies. Molecular & Cellular Proteomics (2024).
4. Detection and quantification of nitric oxide–derived oxidants in biological systems. Journal of Biological Chemistry (2019).