Methylenetetrahydrofolate reductase

Methylenetetrahydrofolate reductase (MTHFR) is an enzyme that exists in the cytoplasm of cells. MTHFR contains a bound flavin cofactor and uses NAD(P)H as the reducing agent.

MTHFR irreversibly reduces 5,10-methylenetetrahydrofolate (substrate) to 5-methyltetrahydrofolate. 5-Methyltetrahydrofolate is used to convert homocysteine (a potentially-toxic amino acid) to methionine by the enzyme methionine synthase.

Polymorphism and role in disease
There is a common DNA sequence variant (polymorphism) in MTHFR at basepair 677 (a change from a C to a T) that results in a thermolabile enzyme with decreased enzymatic activity. Ten percent of the North American population are homozygous for this polymorphism (the incidence is higher in Mediterranean countries and lower in African-Americans). Individuals of 677TT are predisposed to mild hyperhomocysteinemia (high blood homocysteine levels), because they have less MTHFR available to produce 5-methyltetrahydrofolate (which is used to decrease homocysteine). Low dietary intake of the vitamin folic acid can also cause mild hyperhomocysteinemia. This polymorphism and mild hyperhomocysteinemia are associated with neural tube defects in offspring, arterial and venous thrombosis, and cardiovascular disease. It is interesting to note that 677TT individuals are at a decreased risk for certain leukemias and colon cancer, but only when their dietary intake of folate is high. The MTHFR gene could be one of the factors of overall schizophrenia risk. Schizophrenic patients having the risk allele (T\T) show more deficiencies in executive function tasks.

Formula of action


MTHFR = methylenetetrahydrofolate reductase

5,10-CH2-FH4 = 5,10-methylene tetrahydrofolate

5-CH3-FH4 = 5-methyl tetrahydrofolate

NADPH = reduced form of Nicotinamide adenine dinucleotide phosphate

NADP+ = oxidized form of Nicotinamide adenine dinucleotide phosphate