Reactome: A Curated Pathway Database

Defects in cobalamin (B12) metabolism (R-HSA-3296469)

Species Homo sapiens


Cobalamin (Cbl, vitamin B12) is a nutrient essential for normal functioning of the brain and nervous system and for the formation of blood. Cbl-dependent methionine synthase (MTR) is required for conversion of 5-methyltetrahydrofolate (metTHF) to tetrahydrofolate (THF), in addition to its role in conversion of homocysteine to methionine. In Cbl deficiency, and in inborn errors of Cbl metabolism that affect function of methionine synthase, inability to regenerate THF from metTHF results in decreased function of folate-dependent reactions that are involved in 2 steps of purine biosynthesis and thymidylate synthesis. Cbl deficiency results in hyperhomocysteinemia (due to defects in the conversion of homocysteine to methionine which requires Cbl as a cofactor) and increased levels of methylmalonic acid (MMA). Methionine is used in myelin production, protein, neurotransmitter, fatty acid and phospholipid production and DNA methylation. Symptoms of Cbl deficiency are bone marrow promegaloblastosis (megaloblastic anemia) due to the inhibition of DNA synthesis (specifically purines and thymidine) and neurological symptoms. The defective genes involved in Cbl deficiencies are described below (Froese & Gravel 2010, Nielsen et al. 2012, Whitehead 2006, Watkins & Rosenblatt 2011, Fowler 1998).

Locations in the PathwayBrowser
Name Identifier Synonyms
vitamin B12 deficiency 0050731 [cobalamin deficiency, hypocobalaminemia]
Literature References
pubMedId Title Journal Year
21114891 Genetic disorders of vitamin B12 metabolism: eight complementation groups--eight genes Expert Rev Mol Med 2010
16846473 Acquired and inherited disorders of cobalamin and folate in children Br. J. Haematol. 2006
21312325 Inborn errors of cobalamin absorption and metabolism Am J Med Genet C Semin Med Genet 2011
9587028 Genetic defects of folate and cobalamin metabolism Eur. J. Pediatr. 1998
22547309 Vitamin B12 transport from food to the body's cells--a sophisticated, multistep pathway Nat Rev Gastroenterol Hepatol 2012