Methylenetetrahydrofolate reductase

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5,10-methylenetetrahydrofolate reductase (NADPH)
Identifiers
Symbol	MTHFR
HUGO	7436
Entrez	4524
OMIM	607093
RefSeq	NM_005957
UniProt	P42898
Other data
EC number	1.5.1.20
Locus	Chr. 1 p36.3

Methylenetetrahydrofolate reductase (MTHFR) is an enzyme (EC 1.5.1.20) 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.

[edit] 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. 10% of the North American population are homozygous for this polymorphism (the incidence is higher in Mediterranean countries and lower in African-Americans). 677TT individuals 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. Interestingly, 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.^[1] Schizophrenic patients having the risk allele (T\T) show more deficiencies in executive function tasks.^[2]

[edit] 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

Ribbon diagram of the active site of E. coli MTHFR. The flavin cofactor (top) is shown interacting with the bound substrate NADH. Image drawn from PDB 1ZPT

[edit] References

• MTHFR and homocysteine, Dr. Stephan Moll, retrieved 28 December 2004.

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