Which of the following is the primary biochemical role of vitamin B12 that, when deficient, leads to impaired DNA synthesis and megaloblastic anemia?

Explanation

## Vitamin B12 Biochemistry ### Mechanism of Action **Key Point:** Vitamin B12 (cobalamin) functions as a cofactor for methionine synthase, the enzyme that catalyzes the conversion of homocysteine to methionine using 5-methyltetrahydrofolate (5-MTHF) as a methyl donor. ### Why This Matters for DNA Synthesis 1. **Methionine production** → S-adenosylmethionine (SAM) formation 2. **SAM** → universal methyl donor for nucleotide synthesis 3. **Impaired methylation** → defective dTMP synthesis → megaloblastic anemia 4. **Elevated homocysteine** → secondary marker of B12 deficiency ### The "Folate Trap" **High-Yield:** When B12 is deficient, 5-MTHF accumulates and cannot be converted back to tetrahydrofolate (THF). This traps folate in an unusable form, causing **functional folate deficiency** despite normal serum folate levels. This is why B12 and folate deficiencies both cause megaloblastic anemia. ### Clinical Pearl B12 deficiency causes **both** megaloblastic anemia (due to impaired DNA synthesis) **and** neurological damage (due to myelin synthesis impairment via a separate mechanism involving methylmalonyl-CoA mutase). Folate deficiency causes only megaloblastic anemia—no neuropathy. [cite:Harrison 21e Ch 104]