methionine synthase

Methionine synthase (also called 5-methyltetrahydrofolate-homocysteine methyltransferase) links the folate and methionine cycles. It catalyzes the transfer of a methyl group from 5-methyl-THF to homocysteine, forming methionine and regenerating THF. Methylcobalamin (vitamin B12) serves as an essential cofactor, acting as an intermediate methyl carrier during catalysis. Methionine produced is then converted to S-adenosylmethionine (SAM) via methionine adenosyltransferase, and SAM serves as the principal methyl donor for numerous biological methylation reactions (DNA, proteins, neurotransmitters, phospholipids).

Clinical significance: - Vitamin B12 deficiency impairs methionine synthase activity, causing a 'methylfolate trap': 5-methyl-THF accumulates because it cannot be converted back to THF, leading to functional folate deficiency despite normal folate levels. This causes megaloblastic anemia (due to impaired DNA synthesis, since THF is needed for purine and thymidine synthesis) and elevated homocysteine levels. - B12 deficiency also causes neurological symptoms (subacute combined degeneration) due to impaired methylation reactions affecting myelin synthesis, distinguishing it from isolated folate deficiency which does not cause neurological findings. - Nitrous oxide (N2O) anesthesia can irreversibly oxidize the cobalt in B12, inactivating methionine synthase and precipitating or worsening B12 deficiency symptoms, especially in patients with subclinical B12 deficiency. - Elevated homocysteine (from methionine synthase dysfunction) is associated with increased risk of thrombosis and cardiovascular disease. - Rare genetic defects in methionine synthase or its reductase (MTRR) cause homocystinuria with megaloblastic anemia, distinct from cystathionine beta-synthase deficiency (classic homocystinuria).

High-yield board correlations: Understanding this enzyme helps differentiate folate vs. B12 deficiency (both cause elevated homocysteine, but only B12 deficiency also elevates methylmalonic acid, due to a separate B12-dependent reaction catalyzed by methylmalonyl-CoA mutase).