Folic acid: the pathway in the body

This page shows the biochemical pathway behind the laboratory value Folic acid (vitamin B9): 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

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.

The pathway step by step

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. 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. 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. Source 1, 4
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. Source 3, 2
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. Source 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. 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. 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. Source 2

Cofactors in this pathway

• Vitamin B12 — Cofactor of methionine synthase, which moves the methyl group from 5-methyl-THF onto homocysteine 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 Source 2In the ORY catalogue as a laboratory value: Vitamin B6
• Serine — Provides the carbon unit that is handed on within the folate cycle 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 Source 3, 2
• NADPH — Hydrogen donor of DHFR and of MTHFR Source 4, 2
• Zinc — Two zinc atoms in the active site of the folate hydrolase on the brush border of the small intestine 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

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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