Nitrotyrosin (Nitrosativer Stress): the pathway in the body · Biomarker & Blood Analysis

Nitrotyrosin (Nitrosativer Stress) is part of the pathway “Nitrosative stress”. This page shows the whole pathway; the station of Nitrotyrosin (Nitrosativer Stress) is highlighted.

Where this laboratory value sits: 3-Nitrotyrosine — in proteins. 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. It can alter the protein's work. Source 4, 3

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 mark can alter the work of proteins.

The pathway step by step

Each station states what the compound does there. Three signs: ↑ supplies — builds up or makes available · ↓ depletes — inhibits, consumes or withholds · ↕ both, depending on amount. Behind it stands what the statement rests on: established physiology, observed in studies, or contested. The signs do not grade; they name the direction.

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. NO and superoxide form peroxynitrite. Source 1, 2↕ both, depending on amount In small amounts NO is a signalling molecule in blood vessels and nerves. If it meets superoxide, it reacts with it to form peroxynitrite; how much NO and superoxide meet decides which route prevails. established physiology Source 1, 3
   ⚖ When the balance tips

   too much — If cells make a lot of NO while superoxide is present, more peroxynitrite forms, and more 3-nitrotyrosine is left on proteins.

   too little — If little NO forms, less signal reaches blood vessels and nerves; superoxide is then mostly converted by the superoxide dismutases instead of being captured by NO.

   observed in studies · Source 3

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. It oxidises sulphur groups and metal centres. Source 3, 7↓ depletes Peroxynitrite is a strong oxidant: it oxidises sulphur groups in proteins and reacts with metal centres. Via carbon dioxide it releases radicals that nitrate tyrosine. established physiology Source 3, 4
   ⚖ When the balance tips

   too much — If more peroxynitrite forms than peroxiredoxins and glutathione peroxidases can capture, more radicals reach proteins and fats; in cell culture this disturbs the work of the mitochondria.

   too little — If little peroxynitrite forms, hardly any nitration occurs on proteins; immune cells then also use less of this oxidant against microorganisms.

   observed in studies · Source 3, 5

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. Both alter proteins close by. Source 3, 4↓ depletes Nitrogen dioxide and the carbonate radical are short-lived and react close by: they remove electrons from tyrosine and other building blocks and so alter proteins. established physiology Source 3, 4
   ⚖ When the balance tips

   too much — If many radical pairs form, more tyrosine residues are nitrated; some of the radicals are captured beforehand by glutathione and other antioxidants.

   too little — If little carbon dioxide is at hand, fewer radical pairs form; peroxynitrite then reacts more often directly with sulphur groups and metal centres.

   observed in studies · 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. It can alter the protein's work. Source 4, 3↓ depletes The nitro group changes the charge and shape of tyrosine. Depending on the protein, this can inhibit or redirect its work and stop a phosphate group from being attached at this site. observed in studies Source 3, 4
   ⚖ When the balance tips

   too much — If 3-nitrotyrosine accumulates in proteins, more of the affected proteins work in an altered way, and more marked proteins go into breakdown.

   too little — If little 3-nitrotyrosine forms, the tyrosine residues remain free for their usual role, for example as sites for phosphate groups.

   observed in studies · Source 3, 4

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. In this form most of it leaves the body. Source 6↓ depletes The conversion to NHPA turns free nitrotyrosine into a form that the kidney excretes. In this way most of it leaves the body not as nitrotyrosine. observed in studies Source 6
   ⚖ When the balance tips

   too much — If a lot of NHPA forms, it does not come from nitrotyrosine alone: in studies it also arises from nitration of the body's own para-hydroxyphenylacetic acid.

   too little — If little nitrotyrosine is converted to NHPA, a larger share leaves the body unchanged as nitrotyrosine.

   observed in studies · Source 6

6. NHPA → Excretion in urine The kidney releases NHPA and a smaller share of unchanged nitrotyrosine into the urine. With this the breakdown products leave the body. Source 6↓ depletes NHPA and nitrotyrosine leave the body with the urine. This ends the path of nitration; the substances enter no further reaction. observed in studies Source 6
   ⚖ When the balance tips

   too much — If more nitrotyrosine is released, the kidney passes more NHPA and unchanged nitrotyrosine into the urine.

   too little — If little nitrotyrosine is released, the kidney passes correspondingly little NHPA and nitrotyrosine into the urine.

   observed in studies · Source 6

Further stations

• L-arginine — amino acid L-arginine is the starting material for nitric oxide. It supplies the nitrogen atom that later sits in the molecule. NO synthase converts it into NO and citrulline. Source 1↑ supplies Arginine is the only starting material of the NO synthases: they oxidise one of its nitrogen atoms to NO, leaving citrulline. Without arginine no NO forms by this route. established physiology Source 1
  ⚖ When the balance tips

  too much — If a lot of arginine is present, NO synthase is already largely supplied with its starting material; how much NO forms is then decided mainly by calcium and BH4.

  too little — If little arginine is in the cell, NO synthase cannot fully convert the oxygen; in studies it then releases more superoxide, as it does when BH4 is scarce.

  observed in studies · Source 1, 2

• Nitrite — intercepted peroxynitrite Peroxiredoxins and glutathione peroxidases remove an oxygen atom from peroxynitrite. This forms nitrite, which is further converted to nitrate and excreted via the kidney. In this way less peroxynitrite reaches proteins. Source 5↓ depletes Peroxiredoxins and glutathione peroxidases capture peroxynitrite before it nitrates tyrosine. To do so they use up electrons from thioredoxin and glutathione. observed in studies Source 5
  ⚖ When the balance tips

  too much — If the peroxidases capture a lot of peroxynitrite, more thioredoxin and glutathione are oxidised, which the cell must reduce again with NADPH.

  too little — If little selenium or glutathione is available, the glutathione peroxidases capture less peroxynitrite, and more of it reaches the tyrosine residues of proteins.

  observed in studies · Source 5

• Free 3-nitrotyrosine — after protein breakdown When marked proteins are broken down in the proteasome and in lysosomes, 3-nitrotyrosine is released as a single amino acid. It is not built back into proteins. In this way the mark leaves the protein stock. Source 6, 3↓ depletes By breaking down marked proteins, the cell removes the nitration from its protein stock. The released 3-nitrotyrosine is not reused but broken down further. observed in studies Source 6, 3
  ⚖ When the balance tips

  too much — If many marked proteins are broken down, more free 3-nitrotyrosine is released, and more NHPA forms.

  too little — If marked proteins are broken down slowly, 3-nitrotyrosine stays bound in the proteins longer, and less of it is released.

  observed in studies · Source 6, 3

Cofactors in this pathway

• Arginine — Starting material of the NO synthases; the nitrogen atom of NO comes from it; arginine becomes citrulline in the process 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; superoxide and NO form peroxynitrite Source 2
• Iron — Central atom of the haem in the oxygen-binding part of the NO synthases; there it binds and activates oxygen Source 1In the ORY catalogue as a laboratory value: Eisen
• NADPH — Electron source of the NO synthases and of the NADPH oxidases; the oxidases use it to make superoxide Source 1, 7
• FAD and FMN — Pass electrons from NADPH to the haem in the reductase part of NO synthase for NO formation Source 1
• Calcium — Binds to calmodulin; only this complex sets the NO synthases going; so NO forms when needed 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; this yields nitrite Source 5In the ORY catalogue as a laboratory value: Selen
• Glutathione — Provides the glutathione peroxidases with the electrons for this step; it is itself oxidised in the process 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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