One-carbon metabolism

One-Carbon Metabolism - The Methyl Shuffle

One-carbon metabolism transfers single-carbon units for synthesizing nucleotides and amino acids. The main carriers are tetrahydrofolate (THF) and S-adenosylmethionine (SAM), the body's universal methyl donor.

• Tetrahydrofolate (THF): Active form of folate (Vitamin B9); carries 1-carbon units.
• S-adenosylmethionine (SAM): Synthesized from methionine; donates methyl groups ($CH_3$). 📌 SAM the methyl man.
• Vitamin B12 (Cobalamin): Cofactor for methionine synthase, which regenerates methionine from homocysteine.

⭐ Both Vitamin B12 and Folate deficiency lead to ↑ homocysteine, but only B12 deficiency causes an ↑ in methylmalonic acid (MMA).

Folate Cycle - The Leafy Green Engine

• Folate (Vitamin B9) is activated to Tetrahydrofolate (THF) by Dihydrofolate Reductase (DHFR).
• THF is a key one-carbon carrier required for:
  • Thymidylate synthesis: For DNA production ($dUMP \rightarrow dTMP$).
  • Purine synthesis: For DNA and RNA precursors.

⭐ Leucovorin (folinic acid) rescue bypasses the DHFR block by methotrexate, providing a downstream source of THF to replete stores and rescue cells from toxicity.

B12 & Homocysteine - The Critical Connection

• Vitamin B12 (Cobalamin) is a crucial cofactor for two key enzymes:

  • Methionine Synthase: Converts homocysteine to methionine, regenerating tetrahydrofolate. Deficiency traps folate and causes ↑ homocysteine.
  • Methylmalonyl-CoA Mutase: Converts methylmalonyl-CoA to succinyl-CoA. This pathway is essential for fatty acid metabolism.

• Deficiency Markers:

  • ↑ Homocysteine (seen in both B12 & folate deficiency).
  • ↑ Methylmalonic acid (MMA) is specific to B12 deficiency.

• Clinical Impact: ↑ MMA disrupts myelin synthesis in the spinal cord, causing irreversible subacute combined degeneration (sensory and motor deficits).

⭐ Neurological symptoms in megaloblastic anemia are unique to B12 deficiency, not folate deficiency, due to the toxic accumulation of MMA.

📌 Mnemonic: 'Methionine Synthase Saves, Methylmalonyl Mutase Moves.'

Clinical Disorders - Metabolic Mayhem

• Folate (B9) & Vitamin B12 Deficiency:

  • Causes megaloblastic anemia, featuring hypersegmented neutrophils and macrocytic RBCs.
  • Maternal folate deficiency is strongly linked to neural tube defects in the fetus.

• Homocystinuria (Cystathionine Synthase Deficiency):

  • An autosomal recessive disorder leading to elevated homocysteine.
  • Presents with Marfanoid habitus, intellectual disability, thromboembolism, and downward lens dislocation.

⭐ Unlike Marfan syndrome (upward dislocation), the lens in homocystinuria dislocates down and inward.

High‑Yield Points - ⚡ Biggest Takeaways

• One-carbon metabolism is crucial for synthesizing amino acids, purines, and thymidine.
• Tetrahydrofolate (THF), the active form of folate (B9), is the central one-carbon carrier.
• Vitamin B12 is a required cofactor for methionine synthase, which regenerates methionine from homocysteine.
• Deficiencies in B12 or folate cause megaloblastic anemia and ↑ homocysteine.
• Only B12 deficiency leads to neurological deficits due to ↑ methylmalonic acid.
• S-adenosylmethionine (SAM) is the universal methyl donor.