MTRR (methionine synthase reductase) is a critical flavin-dependent oxidoreductase that maintains one-carbon metabolism by reactivating methionine synthase (MTR) through reductive methylation of its inactivated cobalamin cofactor 1. During normal catalysis, MTR-bound cobalamin cycles between active methylcobalamin and inactive cob(II)alamin forms; MTRR reduces the inactive form back to functional cobalamin, preventing enzyme inactivation 1. Additionally, MTRR functions as a molecular chaperone that stabilizes apoMTR and facilitates holoenzyme formation by incorporating methylcobalamin into the apoenzyme 2. MTRR operates within a multiprotein cytosolic complex including MMACHC and MMADHC to safely shuttle cobalamin toward MTR for methionine synthesis 3. Deficiency of MTRR causes homocystinuria with megaloblastic anemia (cblE type) and increases homocysteine accumulation, disrupting folate-dependent methylation reactions essential for epigenetic inheritance and neural development. Clinical studies demonstrate MTRR A66G polymorphisms associate with multiple developmental and cardiovascular outcomes: the variant correlates with improved responses to folinic acid supplementation in autism spectrum disorder 4, influences congenital heart disease risk in Asian populations 5, and affects serum folate levels and cognitive function in preschoolers 6. MTRR variants also show gene-nutrient interactions with alcohol and fruit consumption affecting colorectal cancer survival 7. Geographic variation in MTRR A66G frequency across Chinese populations suggests ethnic-dependent disease susceptibility 8.