Peroxynitrite

Reactions of peroxynitrite leading to either apoptotic or necrotic cell death

Peroxynitrite is a reactive nitrogen species (RNS) with the chemical formula ONOO−. It is an anion, a negatively charged ion, which is a potent oxidant. Peroxynitrite is formed from the reaction of the free radical nitric oxide (NO) with the superoxide radical (O2−). This reaction is fast and competes with the dismutation of superoxide by superoxide dismutase, highlighting the biological significance of peroxynitrite within living organisms.

Formation and Structure

Peroxynitrite is formed in biological systems through the reaction of nitric oxide (NO), which is produced by various nitric oxide synthase enzymes, with superoxide (O2−), which can be generated by multiple pathways, including the mitochondrial electron transport chain and NADPH oxidase activity. The reaction is as follows:

NO + O2− → ONOO−

This reaction is diffusion-limited, meaning it occurs very rapidly, making peroxynitrite a transient species in biological systems. Structurally, peroxynitrite exists in equilibrium with its protonated form, peroxynitrous acid (ONOOH), which can further decompose into various reactive species, including hydroxyl radicals (•OH) and nitrogen dioxide (NO2).

Biological Significance

Peroxynitrite is involved in various physiological and pathological processes. It can modify proteins, lipids, and DNA, leading to cellular damage and death. This modification occurs through direct oxidative reactions or indirect mechanisms, such as the initiation of lipid peroxidation or the nitration of tyrosine residues in proteins.

Physiological Roles

In low concentrations, peroxynitrite may play a role in cellular signaling, similar to its precursor nitric oxide. It has been implicated in the regulation of vascular tone and immune responses. However, the exact physiological functions of peroxynitrite are still under investigation.

Pathological Roles

At higher concentrations, peroxynitrite contributes to oxidative stress, which is associated with various diseases, including neurodegenerative diseases (such as Alzheimer's disease and Parkinson's disease), cardiovascular diseases, and inflammatory diseases. The oxidative and nitrosative stress caused by peroxynitrite can lead to significant cellular and tissue damage, exacerbating disease progression.

Detection and Measurement

Due to its high reactivity and short lifespan, direct measurement of peroxynitrite in biological systems is challenging. Indirect methods, such as the detection of nitrotyrosine residues in proteins, are commonly used as biomarkers of peroxynitrite formation. Various fluorescent probes have also been developed to detect peroxynitrite in living cells and tissues.

Therapeutic Implications

Given its role in oxidative stress and disease, targeting peroxynitrite formation or scavenging peroxynitrite represents a potential therapeutic strategy. Several compounds, including uric acid and some synthetic antioxidants, have been shown to scavenge peroxynitrite or inhibit its formation, offering potential benefits in the treatment of diseases associated with oxidative and nitrosative stress.