4-Hydroxynitrophenyl-Essigsäure (RNS-Marker): the pathway in the body

4-Hydroxynitrophenyl-Essigsäure (RNS-Marker) is part of the pathway “Nitrosative stress”. This page shows the whole pathway; the station of 4-Hydroxynitrophenyl-Essigsäure (RNS-Marker) is highlighted.

Where this laboratory value sits: NHPA — nitrohydroxyphenylacetic acid. Via intermediate steps, this gives rise to 3-nitro-4-hydroxyphenylacetic acid. It is the main breakdown product of free nitrotyrosine. Source 6

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

Whole pathway: Nitrosative stress

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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