methylcobalamin

Methylcobalamin serves as the cofactor for methionine synthase (5-methyltetrahydrofolate-homocysteine methyltransferase) in the cytosol, which remethylates homocysteine to methionine while simultaneously regenerating tetrahydrofolate (THF) from 5-methyl-THF (the 'folate trap' hypothesis explains why B12 deficiency causes secondary folate deficiency). Methionine is subsequently converted to S-adenosylmethionine (SAM), the universal methyl donor required for myelin synthesis, DNA methylation, and neurotransmitter synthesis. Deficiency in this pathway (from B12 deficiency) leads to elevated homocysteine and methylmalonic acid (MMA)—though MMA elevation specifically reflects the mitochondrial adenosylcobalamin-dependent methylmalonyl-CoA mutase pathway, distinguishing B12 deficiency from isolated folate deficiency (where only homocysteine rises, MMA remains normal). Clinically, B12 deficiency (whether from pernicious anemia, malabsorption, strict vegan diets, or metformin use) causes megaloblastic macrocytic anemia, hypersegmented neutrophils, glossitis, and subacute combined degeneration of the spinal cord (affecting dorsal columns and lateral corticospinal tracts), causing loss of vibration/proprioception and spastic paresis—symptoms not corrected by folate alone, making it crucial to distinguish B12 from folate deficiency before treatment. Methylcobalamin, along with cyanocobalamin and hydroxocobalamin, is used therapeutically to treat B12 deficiency, particularly in the U.S. as an alternative to cyanocobalamin, with some evidence for enhanced neurological outcomes given its direct utility in the methylation cycle.