Full mechanism, in text

Carrying carbon pieces for DNA

1 · Dietary folate → THF

Folate in natural food is in polyglutamate form: enriched in dark leafy greens, legumes, liver, and yeast.Fortified foods + supplements contain the synthetic folic acid (monoglutamate) — more stable, more easily absorbed.

Small-intestine brush-border enzymes cleave polyglutamate to monoglutamate → enters the enterocyte via the PCFT transporter → into the portal vein → liver.

Inside hepatocytes, the classic enzyme DHFR (dihydrofolate reductase) reduces folic acid in two steps:

· folic acid → DHF (dihydrofolate)
· DHF → THF (tetrahydrofolate)

THF is the active carrier that actually does the work in the body — every "one-carbon (1C) unit" transport starts from it.

Clinical trivia: methotrexate, used to treat rheumatoid arthritis / leukemia, works by inhibiting DHFR → cells cannot access THF → rapidly proliferating cells (cancer cells, activated lymphocytes) starve first.

2 · THF picks up a 1C unit → 5-MTHF

THF acts like an empty truck, loading and transporting one-carbon groups inside the body — this is the core of "one-carbon metabolism".Source: the serine (Ser) → glycine (Gly) conversion, which transfers a methyl group onto THF.

THF loaded with one-carbon groups at different oxidation states gives rise to multiple active forms:
· 5,10-methylene-THF → synthesizes thymidylate (dTMP) → DNA replication
· 10-formyl-THF → synthesizes purines → DNA + RNA
· 5-methyl-THF () → the only form able to donate the methyl group to

Key bottleneck enzyme: (methylenetetrahydrofolate reductase) — irreversibly reduces 5,10-methylene-THF to 5-MTHF.

MTHFR C677T variant: TT homozygosity (NIH ODS) is found in ~25% of Hispanics, ~10% of Whites and of Asians, and ~1% of African Americans; enzyme activity is reduced. Clinical significance is limited — as long as folate intake is sufficient, there is no need to take "active folate (5-MTHF)" — but marketing claims abound.

3 · Methyl handoff: 5-MTHF + Hcy + B12 → Met + THF

In methionine synthase, passes its methyl group through methyl-B12 to , turning it into methionine, and returns to THF to run the cycle again.The key handoff in the whole cycle — happens at MTR (methionine synthase):

· (carrying -CH₃) enters MTR
· Cofactor: methyl-B12 is the methyl group's "relay station"
· Hcy accepts the methyl → becomes methionine (Met)
· 5-MTHF unloads its methyl → reduced back to THF (the empty truck returns to the cycle)

Significance: this is the body's main pathway to clear Hcy — elevated Hcy is an independent risk factor for cardiovascular and cerebrovascular events.

Met is then activated to (S-adenosyl-methionine) — the body's universal methyl donor:
· Methylation of DNA / histones (epigenetics)
· Synthesis of neurotransmitters (SAM-dependent methylation on some transmitter pathways; methylation of dopamine and serotonin is COMT / ASMT breakdown, not the last step of making them)
· Synthesis of myelin (phosphatidylcholine)
· Synthesis of creatine (guanidinoacetate → creatine)

SAM donates its methyl → becomes SAH → hydrolyzed to Hcy → enters the next cycle.

4 · Folate trap & neural tube defects

Without B12, cannot unload its methyl, so folate gets trapped and megaloblastic anemia follows; separately, folic acid around conception lowers the risk of neural tube defects.Folate trap: when B12 is deficient, the MTR reaction stalls — cannot unload its methyl group — all THF gets trapped methylated as 5-MTHF —

→ shortage of active folate for thymidylate + purine synthesis (DNA)
→ megaloblastic anemia (red cell nucleus matures behind cytoplasm → large but fragile)

This is why giving folate alone can "mask" the hematologic presentation of B12 deficiency, while neurological damage (B12 myelin issue) continues to progress — the IOM for folic acid from fortified food plus supplements is 1,000 µg/day; fortification itself is 140 µg per 100 g grain.

Neural tube defect (NTD) prevention: the 1991 MRC Lancet trial gave hard evidence: 4 mg folic acid/day in women with a prior NTD pregnancy lowered recurrence ~72%. The 400 µg figure is the general-population prevention dose — do not attach the 72% to 400 µg.

· After 1998 US mandatory fortification, the hung NIH ODS sheet records an NTD decline of 28%; Crider 2011 gives a US range of 19-32%
· The critical window is from 1 month preconception → 6 weeks gestation (when most women don't yet realize they are pregnant) → continuous supplementation in women of reproductive age matters more than "start when planning pregnancy"
· Pregnancy = 600 µg/day, upper limit 1000 µg/day (folic acid portion)

Full mechanism, in text

1 · Dietary folate → THF

2 · THF picks up a 1C unit → 5-MTHF

3 · Methyl handoff: 5-MTHF + Hcy + B12 → Met + THF

4 · Folate trap & neural tube defects

Folate · one-carbon cycle & methylation

Full mechanism, in text

1 · Dietary folate → THF

2 · THF picks up a 1C unit → 5-MTHF

3 · Methyl handoff: 5-MTHF + Hcy + B12 → Met + THF

4 · Folate trap & neural tube defects

Folate · one-carbon cycle & methylation