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
Related conditions
Related
- Homocysteine
- S-adenosylmethionine (SAM)
- Methionine synthase
- Cystathionine β-synthase (CBS)
- Dihydrofolate reductase (DHFR)
- 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.
Educational information, not medical advice. For any symptom, see a health professional.
Sources: Metabolism of folate and pterines (Reactome, 2026); Cobalamin (Cbl, vitamin B12) transport and metabolism (Reactome, 2026); Vitamin B12 deficiency anemia: MedlinePlus Medical Encyclopedia (MedlinePlus, US National Library of Medicine, 2026).
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Representative model, for educational purposes only.