Folsäure: the pathway in the body · Biomarker & Blood Analysis

Folsäure is part of the pathway “Folic acid”. This page shows the whole pathway; the station of Folsäure is highlighted.

Where this laboratory value sits: 5-methyl-THF in blood — transport form. In the gut cell and liver, folate is reduced to tetrahydrofolate (THF) and methylated; in the blood it circulates almost only as 5-methyl-THF. Folic acid goes through the same reduction by DHFR, which works slowly in the liver. The rest circulates unchanged. Source 1, 4

In brief

Folic acid is a B vitamin; in foods it occurs as folate. Inside the cell, as tetrahydrofolate, it carries single carbon units - for the building blocks of DNA and RNA and for the methionine cycle. When little folate is available, DNA synthesis stalls and homocysteine builds up.

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. Folate in food → Folate monoglutamate Folate hydrolase An enzyme on the brush border of the small intestine cleaves the glutamate chain until only a single unit remains. Only this form can be absorbed by the intestinal cell. If the chain is not removed, the transporter does not recognise the folate. Source 1↑ supplies The folate hydrolase makes dietary folate absorbable: only the monoglutamate fits the transporter of the gut cell. Folic acid is already a monoglutamate and does not need this step. established physiology Source 1, 7
   ⚖ When the balance tips

   too much — If a lot of monoglutamate sits at the gut surface, it gets in only as fast as the transporter PCFT brings it in; more hydrolase activity does not speed up absorption then.

   too little — If the hydrolase works slowly, more folate remains as polyglutamate; the transporter does not recognise this form, and it passes on through the gut.

   established physiology · Source 1

2. Folate monoglutamate → Into the gut cell PCFT · protons The transporter PCFT moves folate into the cell together with protons. It works best in the slightly acidic environment of the upper small intestine. If the environment is less acidic, less folate gets in. Source 1, 5↑ supplies PCFT is the main entry route for folate in the gut. The protons it carries along drive the transport; absorption therefore depends on the acidic environment at the gut surface. established physiology Source 1, 5
   ⚖ When the balance tips

   too much — Once PCFT is saturated, absorption no longer rises with supply; only with large amounts does additional folate enter the gut cell by a slow, non-saturable route.

   too little — If the environment at the gut surface is less acidic, fewer protons are available to PCFT, and it moves less folate into the cell.

   established physiology · Source 1, 5

3. Into the gut cell → 5-methyl-THF in blood DHFR, MTHFR · NADPH In the gut cell and liver, folate is reduced to tetrahydrofolate (THF) and methylated; in the blood it circulates almost only as 5-methyl-THF. Folic acid goes through the same reduction by DHFR, which works slowly in the liver. The rest circulates unchanged. Source 1, 4↑ supplies 5-methyl-THF is the form in which folate reaches the tissues. Folic acid must first be reduced twice by DHFR to get there; folate from food is mostly already reduced. established physiology Source 1, 4
   ⚖ When the balance tips

   too much — If more folic acid arrives than DHFR in the liver converts, unconverted folic acid appears in the blood; because the enzyme works slowly and at different speeds from person to person, this happens at different amounts.

   too little — If little folate comes from the gut, 5-methyl-THF in the blood falls, and the cells receive less supply for their folate cycle.

   established physiology · Source 4, 1

4. 5-methyl-THF → THF Methionine synthase · vitamin B12 Methionine synthase transfers the methyl group to homocysteine. In the process, 5-methyl-THF becomes THF again – the basic form from which all other folate forms arise. When little THF is free, all downstream building blocks form more slowly. Source 3, 2↑ supplies THF is the free carrier in the folate cycle: it picks up carbon units from serine and passes them on, via its carrier forms, to the building blocks of DNA and RNA and to the methionine cycle. established physiology Source 2, 3
   ⚖ When the balance tips

   too much — If plenty of THF is available, SHMT picks up more carbon units from serine; serine becomes glycine in the process.

   too little — If little THF is free, for instance because folate is trapped as 5-methyl-THF, SHMT picks up fewer carbon units, and all downstream building blocks form more slowly.

   established physiology · Source 2, 3

5. THF → 5,10-methylene-THF SHMT · serine, vitamin B6 (PLP) SHMT transfers a one-carbon unit from serine to THF; its cofactor is vitamin B6. From the product, the enzyme MTHFR with FAD makes 5-methyl-THF again, and the cycle closes. When little of it is available, less dTMP is made. Source 2↑ supplies 5,10-methylene-THF is the switch point of the folate cycle: thymidylate synthase uses it for dTMP, MTHFD1 for purines, MTHFR for 5-methyl-THF. The MTHFR step runs in one direction only. established physiology Source 2, 3
   ⚖ When the balance tips

   too much — If much of it goes through MTHFR, it is fixed as 5-methyl-THF; it returns to the cycle only via methionine synthase, which needs vitamin B12 for this.

   too little — When little 5,10-methylene-THF is available, dTMP formation, purine building and MTHFR share the same scarce pool, and all three routes run more slowly.

   established physiology · Source 3, 2

6. 5,10-methylene-THF → dTMP Thymidylate synthase · dUMP Thymidylate synthase transfers the one-carbon unit to dUMP. This produces dTMP, one of the four building blocks of DNA. When little folate is available, less thymidine is made and DNA synthesis slows. Source 2↑ supplies For dTMP, 5,10-methylene-THF gives up not only a carbon unit but also hydrogen and becomes dihydrofolate; DHFR must reduce it back to THF using NADPH. established physiology Source 2
   ⚖ When the balance tips

   too much — If a lot of dTMP is made, just as much dihydrofolate forms; the cell then needs more DHFR activity and more NADPH to recover its THF.

   too little — When little folate is available, less thymidine is made; without this building block, DNA synthesis slows in cells that are dividing.

   established physiology · Source 2

7. 5,10-methylene-THF → 10-formyl-THF MTHFD1 · NADP+ The enzyme MTHFD1 converts the one-carbon unit into a formyl group. It now sits on nitrogen atom number ten of the folate. The cell needs this formyl group to build purines. Source 2↑ supplies 10-formyl-THF provides the formyl groups for building purines. In the mitochondria, carbon units also give rise to formate, which the cell binds to THF again in the cytoplasm. established physiology Source 2
   ⚖ When the balance tips

   too much — If the cell makes more 10-formyl-THF than purine synthesis needs, it can break down the formyl group via the enzyme ALDH1L and release it as carbon dioxide; NADPH forms in the process.

   too little — When little 10-formyl-THF is available, GART and ATIC obtain fewer formyl groups, and new purines form more slowly.

   established physiology · Source 2

8. 10-formyl-THF → Purine building blocks GART, ATIC Two enzymes of purine synthesis pick up the formyl group from 10-formyl-THF. Purines are building blocks of DNA, RNA and ATP. When little 10-formyl-THF is available, new purines form more slowly. Source 2↑ supplies Two carbon atoms of every newly built purine ring come from 10-formyl-THF. The new synthesis of building blocks for DNA, RNA and ATP thus depends directly on the folate cycle. established physiology Source 2

Further stations

• Folate in food — mostly as polyglutamate Folate is found mainly in green vegetables, pulses and liver. There, a chain of several glutamate units is attached to the core structure. Folic acid is the synthetic form with just one glutamate. The body does not make folate itself. Source 1↑ supplies Food supplies the folate that cells use to transfer carbon units; the body does not make it itself. The polyglutamate from foods must first be shortened, folic acid with its single glutamate need not. established physiology Source 1
  ⚖ When the balance tips

  too much — If a lot of folic acid arrives, it is absorbed quickly in the gut but reduced only slowly by DHFR in the liver; unconverted folic acid then appears in the blood.

  too little — If little folate arrives, less 5-methyl-THF reaches the blood; over time the cells have less THF available for transferring carbon units.

  established physiology · Source 1, 4

• 5-methyl-THF — arrives in the cell Cells bring in 5-methyl-THF via their own transporters. In this form the methyl group is locked in: it is released again in only one single reaction. When little vitamin B12 is available, folate stays trapped in this form. Source 5, 3↑ supplies With 5-methyl-THF the cell receives folate and at the same time a methyl group for homocysteine. It becomes usable for other reactions only once methionine synthase takes the methyl group from it. established physiology Source 5, 3
  ⚖ When the balance tips

  too much — When little vitamin B12 is available, 5-methyl-THF builds up in the cell: the methyl group is not released, folate stays trapped in this form, and other folate forms become scarce.

  too little — If little 5-methyl-THF reaches the cell, methionine synthase receives fewer methyl groups; less homocysteine becomes methionine, and homocysteine builds up.

  established physiology · Source 3

• Homocysteine→methionine — the other side of the reaction The same reaction has two sides. As 5-methyl-THF gives up its methyl group, homocysteine accepts it and becomes methionine. Without vitamin B12 as a cofactor, the reaction comes to a halt. If it stalls, homocysteine builds up. Source 3↑ supplies The reaction removes homocysteine and supplies methionine, from which SAM forms, the methyl group donor of many reactions. SAM in turn inhibits MTHFR and so slows the supply of 5-methyl-THF. established physiology Source 3
  ⚖ When the balance tips

  too much — If a lot of methionine and thus SAM forms, SAM inhibits MTHFR; less 5-methyl-THF is then made, and more folate remains for the building blocks of DNA and RNA.

  too little — If this reaction stalls, homocysteine builds up, less methionine and less SAM form, and folate stays trapped as 5-methyl-THF.

  established physiology · Source 3, 2

Cofactors in this pathway

• Vitamin B12 — Cofactor of methionine synthase, which moves the methyl group from 5-methyl-THF onto homocysteine, freeing THF Source 3In the ORY catalogue as a laboratory value: Vitamin B12
• Vitamin B6 — Cofactor (PLP) of SHMT, which moves a carbon unit from serine onto THF; this forms 5,10-methylene-THF Source 2In the ORY catalogue as a laboratory value: Vitamin B6
• Serine — Provides the carbon unit that is handed on within the folate cycle; glycine forms in the process Source 2In the ORY catalogue as a laboratory value: Serin
• Vitamin B2 (FAD) — Flavin cofactor of MTHFR, which converts 5,10-methylene-THF into 5-methyl-THF; this step is irreversible Source 3, 2
• NADPH — Hydrogen donor of DHFR and of MTHFR; without hydrogen, reduction to THF stalls Source 4, 2
• Zinc — Two zinc atoms in the active site of the folate hydrolase on the brush border of the small intestine; needed for uptake Source 7, 1In the ORY catalogue as a laboratory value: Zink

What acts on this pathway

• Methotrexate — Methotrexate inhibits dihydrofolate reductase. As a result, less folate is converted into the reduced form the cell works with; this mechanism is described in pharmacology. Source 6

Sources

1. Visentin M, Diop-Bove N, Zhao R et al. The intestinal absorption of folates. Annu Rev Physiol 2014 · PubMed 24512081
2. Ducker GS, Rabinowitz JD. One-Carbon Metabolism in Health and Disease. Cell Metab 2017 · PubMed 27641100
3. Froese DS, Fowler B, Baumgartner MR. Vitamin B12, folate, and the methionine remethylation cycle - biochemistry, pathways, and regulation. J Inherit Metab Dis 2019 · PubMed 30693532
4. Bailey SW, Ayling JE. The extremely slow and variable activity of dihydrofolate reductase in human liver and its implications for high folic acid intake. Proc Natl Acad Sci U S A 2009 · PubMed 19706381
5. Zhao R, Diop-Bove N, Visentin M et al. Mechanisms of membrane transport of folates into cells and across epithelia. Annu Rev Nutr 2011 · PubMed 21568705
6. Maksimovic V, Pavlovic-Popovic Z, Vukmirovic S et al. Molecular mechanism of action and pharmacokinetic properties of methotrexate. Mol Biol Rep 2020 · PubMed 32415503
7. Vorlova B, Knedlik T, Tykvart J et al. GCPII and its close homolog GCPIII: from a neuropeptidase to a cancer marker and beyond. Front Biosci (Landmark Ed) 2019 · PubMed 30844704

Whole pathway: Folic acid

Related pathways

• Methylation: methionine and homocysteine — 5-methyl-thf
• Glycine and serine — 5,10-methylene-thf
• Branched-chain amino acids — Vitamin B12, Vitamin B6
• Iron and ferritin — Vitamin B6, Zink
• Glutathione — Vitamin B6, Serin

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