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[Biochemistry](https://durgical.com/en/biochemistry/) · Topic

# One-carbon metabolism (folate, B12 and SAM)

Folate and vitamin B12 move one-carbon groups to make DNA and methylate molecules; when they fail, megaloblastic anaemia and high homocysteine appear.

Updated 2026-11-01

## Key facts

- Tetrahydrofolate (THF) carries one-carbon units (methyl, methylene, formyl) at several oxidation states.
- Serine is the main source of these units (serine hydroxymethyltransferase, with B6).
- Three destinations: purines, thymidylate (dTMP) and methionine/SAM.
- Only methionine synthase, with B12, recovers THF from 5-methyl-THF.

## In detail

- Dietary folate is reduced to THF by dihydrofolate reductase.
- Serine gives one carbon and 5,10-methylene-THF forms.
- Thymidylate synthase uses that carbon to turn dUMP into dTMP; folate leaves as DHF and DHFR reduces it again.
- MTHFR reduces 5,10-methylene-THF to 5-methyl-THF, a practically irreversible step.
- Methionine synthase passes that methyl to homocysteine (with B12), forming methionine.
- Methionine with ATP forms SAM, which gives its methyl to DNA, proteins, creatine, adrenaline and phospholipids; homocysteine is left.
- Without B12 folate is trapped as 5-methyl-THF: there is not enough THF for DNA even though folate is present.

## Clinical notes

- Folate or B12 deficiency causes megaloblastic anaemia; only B12 deficiency gives nerve damage and high methylmalonic acid.
- Methotrexate (DHFR), 5-fluorouracil (thymidylate synthase) and trimethoprim act on this cycle.
- Folate before conception lowers neural tube defects.
- Mild MTHFR variants raise homocysteine slightly.

## Pathways

- [Methionine cycle and transsulfuration](https://durgical.com/en/biochemistry/pathways/methionine-cycle-and-transsulfuration/)

## Related conditions

- [Homocystinuria](https://durgical.com/en/conditions/homocystinuria/)
- [Methylmalonic acidaemia](https://durgical.com/en/conditions/methylmalonic-acidaemia/)
- [Spina bifida (myelomeningocele)](https://durgical.com/en/conditions/spina-bifida/)

## Related

- [Homocysteine](https://durgical.com/en/biochemistry/molecules/homocysteine/)
- [S-adenosylmethionine (SAM)](https://durgical.com/en/biochemistry/molecules/s-adenosylmethionine/)
- [Methionine synthase](https://durgical.com/en/biochemistry/enzymes/methionine-synthase/)
- [Cystathionine β-synthase (CBS)](https://durgical.com/en/biochemistry/enzymes/cystathionine-synthase/)
- [Dihydrofolate reductase (DHFR)](https://durgical.com/en/biochemistry/enzymes/dihydrofolate-reductase/)
- [Thymidylate synthase](https://durgical.com/en/biochemistry/enzymes/thymidylate-synthase/)

## Test yourself

Think of the answer, then tap the question to see it.

## What is the main source of one-carbon units for folate?

Serine, which gives its carbon to THF, forming 5,10-methylene-THF and glycine.

## Why does B12 deficiency cause megaloblastic anaemia when folate is present?

Folate is trapped as 5-methyl-THF, so THF is short for making thymidylate and purines.

## Which test separates B12 deficiency from folate deficiency?

Methylmalonic acid: high in B12 deficiency and normal in folate deficiency; homocysteine rises in both.

## Which enzyme of the cycle does methotrexate block?

Dihydrofolate reductase, which regenerates THF; without it DNA synthesis slows.

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Educational information, not medical advice. For any symptom, see a health professional.

Sources: [Metabolism of folate and pterines](https://reactome.org/PathwayBrowser/#/R-HSA-196757) (Reactome, 2026); [Cobalamin (Cbl, vitamin B12) transport and metabolism](https://reactome.org/PathwayBrowser/#/R-HSA-196741) (Reactome, 2026); [Vitamin B12 deficiency anemia: MedlinePlus Medical Encyclopedia](https://medlineplus.gov/ency/article/000574.htm) (MedlinePlus, US National Library of Medicine, 2026).

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Source: https://durgical.com/en/biochemistry/topics/one-carbon-metabolism/
License: CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). Cite as: DurgiPedia (durgical.com), https://durgical.com/en/biochemistry/topics/one-carbon-metabolism/