What are the co-factors of Vitamin B12?

Vitamin B12 Co-factors

Vitamin B12 functions as a cofactor for only two enzymatic reactions in humans: methionine synthase (which requires 5-methyltetrahydrofolate as a co-substrate) and methylmalonyl-CoA mutase. 1, 2

Primary Enzymatic Reactions Requiring B12

Methionine Synthase Pathway

• Vitamin B12 (as methylcobalamin) serves as an essential cofactor for methionine synthase, which catalyzes the conversion of homocysteine to methionine 1
• 5-methyltetrahydrofolate (active folate/vitamin B9) acts as the methyl donor in this reaction, transferring its methyl group to homocysteine 1
• This reaction is critical for DNA synthesis through the production of purines and pyrimidines 3
• Riboflavin (vitamin B2) is required as a cofactor for methylenetetrahydrofolate reductase (MTHFR), the enzyme that produces 5-methyltetrahydrofolate 1

Methylmalonyl-CoA Mutase Pathway

• Vitamin B12 (as adenosylcobalamin) functions as a cofactor for methylmalonyl-CoA mutase in the mitochondria 2
• This enzyme converts methylmalonyl-CoA to succinyl-CoA in fatty acid metabolism 1
• Riboflavin is also required in the β-oxidation pathway where flavins serve as electron acceptors 1

Additional Co-factors in Homocysteine Metabolism

Transsulfuration Pathway

• Vitamin B6 (as pyridoxal phosphate) is an essential cofactor for cystathionine-β-synthase (CBS), the enzyme responsible for converting homocysteine to cystathionine and ultimately to cysteine 1
• Riboflavin serves as a cofactor for enzymes in the transsulfuration pathway 1

Alternative Remethylation

• Betaine acts as an alternative methyl donor for homocysteine remethylation through betaine-homocysteine methyltransferase 1

Functional Interdependence: The "Methyl Trap"

B12 deficiency creates a "methyl trap" where 5-methyltetrahydrofolate accumulates and cannot participate in one-carbon transfer reactions, leading to functional folate deficiency even when folate levels appear normal 1, 3

• This interdependence means that vitamin B12 deficiency leads to functional vitamin B9 deficiency by reducing methionine synthase activity and causing 5-MTHF accumulation 1
• Assessment of vitamin B9 status should include estimation of vitamin B12 status due to this functional overlap 1

Clinical Implications of Co-factor Deficiencies

Combined Deficiency Effects

• Deficiency of folate (5-MTHF), B12, or B6 has significant implications for vascular health through hyperhomocysteinemia 1
• Vitamin B12 status (as well as vitamin B6) has been significantly associated with length of stay in rehabilitation following injury, related to muscle mass and function decline 1

Supplementation Considerations

• Future studies should use methylcobalamin and 5-methyltetrahydrofolate instead of cyanocobalamin and folic acid, with possible addition of vitamin B6 and riboflavin 1
• Never administer folic acid before treating B12 deficiency, as it may mask anemia while allowing irreversible neurological damage to progress 4