Glutathion (GSH): the pathway in the body · Biomarker & Blood Analysis

Glutathion (GSH) is part of the pathway “Glutathione”. This page shows the whole pathway; the station of Glutathion (GSH) is highlighted.

Where this laboratory value sits: Glutathione (GSH) — made of three building blocks. Glutathione synthetase adds glycine. The result is glutathione – a small molecule made of glutamate, cysteine and glycine that is present in every cell. The liver also releases it into the blood. Source 1

In brief

Glutathione is a small molecule made of the three amino acids glutamate, cysteine and glycine. Through the sulfur group of its cysteine it hands hydrogen to peroxides; enzymes also attach it to foreign substances, which are then excreted. Oxidised glutathione is recycled.

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. Homocysteine → Cystathionine CBS · vitamin B6 (PLP), serine Cystathionine β-synthase (CBS) joins homocysteine to serine. The enzyme works with pyridoxal phosphate, the active form of vitamin B6, and also carries a haem group. From here the sulphur no longer returns to methionine. Source 2↑ supplies Cystathionine holds the sulphur of homocysteine until CSE releases cysteine from it. Once it is formed, the route is fixed: this sulphur no longer returns to methionine. established physiology Source 2
   ⚖ When the balance tips

   too much — If cystathionine builds up because CSE works more slowly, more of it passes into the urine, and less cysteine is formed.

   too little — If little cystathionine forms, for example because little PLP is available for CBS, less sulphur runs towards cysteine, and homocysteine stays longer in the methionine cycle.

   established physiology · Source 2

2. Cystathionine → Cysteine CSE · vitamin B6 (PLP) Cystathionine γ-lyase (CSE) splits cystathionine, releasing cysteine. Cysteine also comes from food and is the building block in shortest supply for glutathione production. When little cysteine is available, less glutathione forms. Source 2, 1↑ supplies Cysteine supplies the sulphur group that makes glutathione active. Because it is usually the scarcest building block, its supply, together with GCL, determines how much glutathione the cell can make. established physiology Source 1
   ⚖ When the balance tips

   too much — If more cysteine is present than glutathione synthesis needs, the excess is broken down, among other things to taurine, sulphate and hydrogen sulphide; outside the cell cysteine quickly oxidises to cystine.

   too little — If little cysteine is available, the cell makes less glutathione, even when glutamate, glycine and ATP are plentiful.

   established physiology · Source 1, 2

3. Cysteine → γ-glutamylcysteine GCL · glutamate, ATP Glutamate-cysteine ligase (GCL) links glutamate and cysteine through an unusual bond. This step sets the pace of the whole pathway and uses ATP. Finished glutathione slows GCL by feedback. Source 1↑ supplies GCL sets the pace of glutathione synthesis. Finished glutathione inhibits it by feedback; when the glutathione pool falls, the inhibition eases and this step runs faster. established physiology Source 1
   ⚖ When the balance tips

   too much — If γ-glutamylcysteine builds up because glutathione synthetase cannot keep pace, it is converted to 5-oxoproline, which is excreted in the urine.

   too little — If little γ-glutamylcysteine forms because cysteine or ATP is scarce, the downstream synthetase makes correspondingly less glutathione; it is itself rarely the bottleneck.

   established physiology · Source 1

4. γ-glutamylcysteine → Glutathione (GSH) Glutathione synthetase · glycine, ATP Glutathione synthetase adds glycine. The result is glutathione – a small molecule made of glutamate, cysteine and glycine that is present in every cell. The liver also releases it into the blood. Source 1↑ supplies Glutathione supplies electrons for the peroxidases and the binding partner for the transferases. The liver makes a particularly large amount and releases it into the blood; other tissues recover cysteine from it. established physiology Source 1
   ⚖ When the balance tips

   too much — If a lot of glutathione is present, it inhibits GCL and so slows its own synthesis; the cell thereby keeps its pool within a narrow range.

   too little — If little glutathione is available, the feedback inhibition of GCL eases, and via Nrf2 the cell makes more enzymes of glutathione synthesis; until then peroxides and foreign compounds are processed more slowly.

   established physiology · Source 1

5. Hydrogen peroxide → Water GPx · selenium Glutathione peroxidases transfer hydrogen from two GSH molecules to hydrogen peroxide, which becomes water. These enzymes carry selenium in their active site. Two GSH are used up per molecule of peroxide. Source 3↓ depletes With the formation of water the peroxide is defused. For this, glutathione peroxidase uses up two molecules of GSH per molecule of hydrogen peroxide. established physiology Source 3
   ⚖ When the balance tips

   too much — If a lot of peroxide passes through this reaction, a correspondingly large amount of GSH becomes GSSG; glutathione reductase must then use more NADPH to recover it.

   too little — If the reaction runs slowly, for example because little selenium is available for the peroxidase, hydrogen peroxide persists longer; enzymes such as catalase and peroxiredoxins then handle part of it.

   established physiology · Source 3, 4

6. GSH → GSSG In this reaction, two GSH molecules join via their sulphur atoms to form GSSG, glutathione disulphide. If GSSG builds up, the cell exports it and so loses glutathione. Source 3, 4↓ depletes GSSG is spent glutathione. If it accumulates, it can attach glutathione to sulphur groups of proteins and alter their activity; many cells also export it. established physiology Source 4, 1
   ⚖ When the balance tips

   too much — If GSSG builds up because the reductase cannot keep pace, the cell exports it and thereby loses glutathione; at the same time more proteins carry glutathione as a tag.

   too little — If little GSSG forms, little peroxide is currently being broken down via this route; the ratio then lies far on the side of GSH.

   established physiology · Source 4, 1

7. GSSG → GSH regenerated Glutathione reductase · NADPH, FAD (vitamin B2) Glutathione reductase splits GSSG back into two GSH. It does this by transferring hydrogen from NADPH and carries FAD, which is derived from vitamin B2. So not every molecule has to be made anew. Source 4↑ supplies The reductase recovers GSH without new glutathione having to be made. It needs NADPH for this, which comes mainly from the pentose phosphate pathway; the cycle thus depends on sugar metabolism. established physiology Source 4
   ⚖ When the balance tips

   too much — If the reductase recovers plenty of GSH, almost all glutathione is in the reduced form, and hardly any GSSG is exported from the cell.

   too little — If little GSH is recovered because NADPH or FAD is scarce, GSSG accumulates, and the cell has to replace glutathione through slower new synthesis.

   established physiology · Source 4, 1

8. Foreign compound → GSH conjugate GST · GSH Glutathione S-transferases (GST) link glutathione to the foreign compound. The product is more water-soluble than the starting substance and is exported from the cell. For a few substances the product is more reactive than the starting substance. Source 5↕ both, depending on amount Usually the conjugate is less reactive than the starting substance and is moved out of the cell by transporters. With some substances, such as dihaloalkanes, a more reactive product forms instead. established physiology Source 5
   ⚖ When the balance tips

   too much — If conjugates accumulate in the cell because export cannot keep pace, they inhibit the glutathione S-transferases; the pathway then slows itself.

   too little — If little conjugate forms because little glutathione or little transferase activity is available, the foreign compound remains reactive longer and forms other bonds.

   observed in studies · Source 5

9. GSH conjugate → Mercapturic acid Peptidases, NAT · acetyl-CoA Peptidases trim the conjugate down to the cysteine residue; an acetyl group is added. As mercapturic acid, the substance leaves the body in the urine. A cysteine residue leaves the body with it. Source 5, 4↓ depletes With mercapturic acid the foreign compound leaves the body. The glutamate and glycine of glutathione are split off beforehand and reused; the cysteine residue leaves with it. established physiology Source 5
   ⚖ When the balance tips

   too much — If a lot of mercapturic acid is excreted, a cysteine residue leaves the body with each molecule; this sulphur must be replenished from food or transsulfuration.

   too little — If little mercapturic acid forms, little foreign compound is currently being bound via this route, and the cysteine residue stays in the body.

   established physiology · Source 5, 2

Further stations

• Homocysteine — from methionine conversion Homocysteine arises when the amino acid methionine is converted. Part of it enters the transsulfuration pathway, which leads to cysteine. When plenty of S-adenosylmethionine is present, more of it goes to cysteine. Source 2↑ supplies Homocysteine supplies the sulphur for cysteine via the transsulfuration pathway. Whether it goes there or back to methionine is regulated by S-adenosylmethionine: when plenty of it is present, it switches on CBS. established physiology Source 2
  ⚖ When the balance tips

  too much — If homocysteine builds up because neither the path to cysteine nor the one back to methionine keeps pace, more of it passes from the cells into the blood.

  too little — If little homocysteine is available, less sulphur flows into the transsulfuration pathway; the cysteine for glutathione must then come more from food.

  established physiology · Source 2, 1

• GSH — reduced form In the cell, glutathione is mostly present in its reduced form. The SH group of cysteine can give up hydrogen; the following reactions are based on this. It thus keeps the cell interior in a reduced state. Source 4↑ supplies Reduced glutathione gives electrons to peroxidases and to proteins whose sulphur groups have been oxidised. It thus keeps the cell interior reduced; how strongly depends on the ratio of GSH to GSSG. established physiology Source 4
  ⚖ When the balance tips

  too much — If GSH strongly outweighs GSSG, glutaredoxins quickly remove glutathione tags from proteins again; switching events via oxidised sulphur groups then occur less often.

  too little — If little GSH is available, the ratio shifts towards GSSG; more sulphur groups in proteins stay oxidised or carry glutathione as a tag, and enzymes with such groups change their activity.

  observed in studies · Source 4

• Hydrogen peroxide — by-product of metabolism Hydrogen peroxide is formed continuously when cells use oxygen. If it is not converted, it can alter fatty acids and proteins. In small amounts it also serves the cell as a messenger. Source 3↕ both, depending on amount In small amounts hydrogen peroxide acts as a messenger that switches enzymes on and off via their sulphur groups; in larger amounts it oxidises fatty acids and proteins. The peroxidases determine how long it remains. observed in studies Source 3
  ⚖ When the balance tips

  too much — If hydrogen peroxide builds up, it oxidises sulphur groups in proteins and fatty acids in membranes; at the same time more GSH is used up and turned into GSSG.

  too little — If there is very little hydrogen peroxide, signals are missing by which cells respond, for example, to growth factors and insulin; a cell is never entirely free of it.

  observed in studies · Source 3

• Foreign compound — xenobiotic molecule Many substances foreign to the body, and their breakdown products, have a site to which sulphur can attach. Glutathione intercepts such substances and is used up in the process. Source 5↓ depletes Electrophilic foreign compounds, i.e. substances that pull electrons towards themselves, react with sulphur groups of proteins and with DNA. Glutathione intercepts them and is itself used up in the process. established physiology Source 5
  ⚖ When the balance tips

  too much — If a large amount of such a compound arrives at once, glutathione is used up faster than the cell can make it; the remaining compound then binds to the cell's proteins.

  too little — If little of it arrives, cells make the transferases at their basal level; only reactive compounds switch on the production of further transferases via Nrf2.

  established physiology · Source 5, 6

Cofactors in this pathway

• Cysteine — Building block of glutathione and the part that runs short first; with little of it, less glutathione forms Source 1, 2
• Glutamate — Building block of glutathione; GCL joins it to cysteine; this step sets the pace Source 1In the ORY catalogue as a laboratory value: Glutamat
• Glycine — Building block of glutathione; glutathione synthase adds it last; without glycine no finished glutathione Source 1In the ORY catalogue as a laboratory value: Glycin
• Vitamin B6 — Cofactor (PLP) of CBS and CSE on the way from homocysteine to cysteine; with little PLP, less cysteine forms Source 2In the ORY catalogue as a laboratory value: Vitamin B6
• Selenium — Present as selenocysteine in the active site of the glutathione peroxidases; when scarce, peroxide breakdown slows Source 3In the ORY catalogue as a laboratory value: Selen
• NADPH — Hydrogen donor of glutathione reductase, which turns GSSG back into two GSH; when scarce, GSSG builds up Source 4
• Vitamin B2 (FAD) — Flavin cofactor of glutathione reductase; with little FAD, less GSH is regenerated Source 4
• Serine — Partner of homocysteine in the CBS reaction that leads to cystathionine; without serine no cystathionine forms Source 2In the ORY catalogue as a laboratory value: Serin

What acts on this pathway

• Paracetamol — When paracetamol is broken down in the liver, the reactive intermediate NAPQI is formed. Glutathione S-transferases bind it to glutathione for excretion; glutathione is used up in the process. Source 6

Sources

1. Lu SC. Glutathione synthesis. Biochim Biophys Acta 2013 · PubMed 22995213
2. Sbodio JI, Snyder SH, Paul BD. Regulators of the transsulfuration pathway. Br J Pharmacol 2019 · PubMed 30007014
3. Brigelius-Flohé R, Maiorino M. Glutathione peroxidases. Biochim Biophys Acta 2013 · PubMed 23201771
4. Deponte M. Glutathione catalysis and the reaction mechanisms of glutathione-dependent enzymes. Biochim Biophys Acta 2013 · PubMed 23036594
5. Hayes JD, Flanagan JU, Jowsey IR. Glutathione transferases. Annu Rev Pharmacol Toxicol 2005 · PubMed 15822171
6. Rushworth GF, Megson IL. Existing and potential therapeutic uses for N-acetylcysteine: the need for conversion to intracellular glutathione for antioxidant benefits. Pharmacol Ther 2014 · PubMed 24080471

Whole pathway: Glutathione

Related pathways

• Methylation: methionine and homocysteine — homocysteine
• 8-OHdG — hydrogen peroxide
• Selenium — hydrogen peroxide
• Vitamin B2 — gsh
• Vitamin B6 — homocysteine

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