Which of the following is the primary biochemical defect in vitamin B12 deficiency that leads to impaired DNA synthesis?

Explanation

## Vitamin B12 and DNA Synthesis **Key Point:** Vitamin B12 (cobalamin) is an essential cofactor for methionine synthase, the enzyme that catalyzes the conversion of homocysteine to methionine using methyltetrahydrofolate as the methyl donor. ### Mechanism of B12 Deficiency When B12 is deficient: 1. Methionine synthase activity decreases 2. Homocysteine accumulates (hyperhomocysteinemia) 3. Methyltetrahydrofolate becomes trapped and cannot be converted to tetrahydrofolate (THF) 4. THF is required for purine and pyrimidine synthesis 5. **Result:** Impaired DNA synthesis → megaloblastic anemia **High-Yield:** This is why B12 deficiency causes **megaloblastic anemia** — the same morphologic finding as folate deficiency. Both deficiencies impair DNA synthesis, causing nuclear maturation to lag behind cytoplasmic maturation. **Mnemonic:** **"B12 → Methionine → Methylation → DNA"** — B12 enables the methylation cycle, which is essential for nucleotide synthesis. ### Clinical Pearl B12 deficiency also causes **neurologic manifestations** (subacute combined degeneration) because methionine is required for myelin formation. Folate deficiency does NOT cause neurologic symptoms — this is a key differentiator.