Nitrosative stress: the pathway in the body

This page shows the biochemical pathway behind the laboratory value Nitrotyrosine: which stations follow one another, which enzymes carry out each step and which cofactors they use. Every statement has a source. The page describes general textbook knowledge and says nothing about any individual person.

In brief

Nitrosative stress describes reactions of nitric oxide and its products with proteins. When NO meets superoxide, peroxynitrite forms and leaves 3-nitrotyrosine on tyrosine residues.

The pathway step by step

1. L-arginine → Nitric oxide NO synthase · BH4, haem, NADPH, O₂ NO synthases convert arginine with oxygen into nitric oxide and citrulline. They need NADPH, haem iron and the cofactor tetrahydrobiopterin (BH4). NO acts as a signalling molecule, for example in blood vessels and nerves. Source 1, 2
2. Nitric oxide → Peroxynitrite · Superoxide (O₂•⁻) When NO meets the superoxide radical, the two combine to form peroxynitrite at almost every encounter. Superoxide arises in mitochondria and from the NADPH oxidases of immune cells. Source 3, 7
3. Peroxynitrite → Radical pair · Carbon dioxide (CO₂) In the body, peroxynitrite usually reacts first with carbon dioxide. The resulting intermediate splits into two radicals: nitrogen dioxide and the carbonate radical. Source 3, 4
4. Radical pair → 3-Nitrotyrosine · Tyrosine in protein The carbonate radical removes an electron from the amino acid tyrosine; nitrogen dioxide then attaches to the resulting tyrosyl radical. What remains is 3-nitrotyrosine, a lasting mark on the protein. Source 4, 3
5. Free 3-nitrotyrosine → NHPA Via intermediate steps, this gives rise to 3-nitro-4-hydroxyphenylacetic acid. It is the main breakdown product of free nitrotyrosine. Source 6
6. NHPA → Excretion in urine The kidney releases NHPA and a smaller share of unchanged nitrotyrosine into the urine. Source 6

Cofactors in this pathway

• Arginine — Starting material of the NO synthases; the nitrogen atom of NO comes from it Source 1In the ORY catalogue as a laboratory value: Arginin
• Tetrahydrobiopterin (BH4) — Cofactor of the NO synthases; without it they release superoxide instead of NO Source 2
• Iron — Central atom of the haem in the oxygen-binding part of the NO synthases Source 1In the ORY catalogue as a laboratory value: Eisen
• NADPH — Electron source of the NO synthases and of the NADPH oxidases Source 1, 7
• FAD and FMN — Pass electrons from NADPH to the haem in the reductase part of NO synthase Source 1
• Calcium — Binds to calmodulin; only this complex sets the NO synthases going Source 1In the ORY catalogue as a laboratory value: Calcium (intrazellulär)
• Selenium — Building block of the glutathione peroxidases that remove an oxygen atom from peroxynitrite Source 5In the ORY catalogue as a laboratory value: Selen
• Glutathione — Provides the glutathione peroxidases with the electrons for this step Source 5In the ORY catalogue as a laboratory value: Glutathion (GSH)

Sources

1. Andrew PJ, Mayer B. Enzymatic function of nitric oxide synthases. Cardiovasc Res 1999 · PubMed 10690324
2. Tejero J, Stuehr D. Tetrahydrobiopterin in nitric oxide synthase. IUBMB Life 2013 · PubMed 23441062
3. Ferrer-Sueta G, Campolo N, Trujillo M et al. Biochemistry of Peroxynitrite and Protein Tyrosine Nitration. Chem Rev 2018 · PubMed 29400454
4. Bartesaghi S, Radi R. Fundamentals on the biochemistry of peroxynitrite and protein tyrosine nitration. Redox Biol 2018 · PubMed 29154193
5. Trujillo M, Ferrer-Sueta G, Radi R. Peroxynitrite detoxification and its biologic implications. Antioxid Redox Signal 2008 · PubMed 18500925
6. Mani AR, Pannala AS, Orie NN et al. Nitration of endogenous para-hydroxyphenylacetic acid and the metabolism of nitrotyrosine. Biochem J 2003 · PubMed 12797864
7. Babior BM. NADPH oxidase. Curr Opin Immunol 2004 · PubMed 14734109

Related pathways

• Arginine and nitric oxide — nitric oxide
• 8-OHdG — Eisen, Selen
• Omega-6 fatty acids and eicosanoids — Eisen, Calcium (intrazellulär)
• Vitamin C — Eisen, Selen
• Borrelia — Eisen, Selen

As of 2026-09-16. Draft, written by Claude to schema v2; sources checked in PubMed; expert approval pending
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