Methylenetetrahydrofolate reductase: biochemical characterization and medical significance

Curr Pharm Des. 2013;19(14):2574-93. doi: 10.2174/1381612811319140008.


Methylenetetrahydrofolate reductase (MTHFR) catalyzes the reduction of 5,10-methylenetetrahydofolate (CH2-H4folate) to 5-methyltetrahydrofolate (CH3-H4folate). The enzyme employs a noncovalently-bound flavin adenine dinucleotide (FAD), which accepts reducing equivalents from NAD(P)H and transfers them to CH2-H4folate. The reaction provides the sole source of CH3-H4folate, which is utilized by methionine synthase in the synthesis of methionine from homocysteine. MTHFR plays a key role in folate metabolism and in the homeostasis of homocysteine; mutations in the enzyme lead to hyperhomocyst(e)inemia. A common C677T polymorphism in MTHFR has been associated with an increased risk for the development of cardiovascular disease, Alzheimer's disease, and depression in adults, and of neural tube defects in the fetus. The mutation also confers protection for certain types of cancers. This review presents the current knowledge of the enzyme, its biochemical characterization, and medical significance.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Allosteric Regulation
  • Amino Acid Sequence
  • Animals
  • Arabidopsis / enzymology
  • Cardiovascular Diseases / enzymology
  • Catalysis
  • Escherichia coli / enzymology
  • Homocysteine / metabolism
  • Humans
  • Hyperhomocysteinemia* / enzymology
  • Hyperhomocysteinemia* / genetics
  • Leishmania major / enzymology
  • Mental Disorders / enzymology
  • Methylenetetrahydrofolate Reductase (NADPH2)* / chemistry
  • Methylenetetrahydrofolate Reductase (NADPH2)* / deficiency
  • Methylenetetrahydrofolate Reductase (NADPH2)* / genetics
  • Methylenetetrahydrofolate Reductase (NADPH2)* / metabolism
  • Models, Molecular
  • Molecular Sequence Data
  • Neoplasms / enzymology
  • Neural Tube Defects / enzymology
  • Polymorphism, Single Nucleotide*
  • Sequence Alignment
  • Tetrahydrofolates / metabolism


  • Tetrahydrofolates
  • Homocysteine
  • Methylenetetrahydrofolate Reductase (NADPH2)