Dihydrofolate reductase

Dihydrofolate reductase, or DHFR, reduces dihydrofolic acid to tetrahydrofolic acid, using NADPH as electron donor, which can be converted to the kinds of tetrahydrofolate cofactors used in 1-carbon transfer chemistry.

Clinical significance

Because tetrahydrofolate, the product of this reaction, is the active form of folate in humans, inhibition of DHFR can cause functional folate deficiency. Because folate is needed by rapidly dividing cells to make thymine, this effect may be therapeutic. For example, methotrexate is used as cancer chemotherapy because it can prevent neoplastic cells from dividing.

A variety of drugs act on dihydrofolate reductase:

• the antibiotic trimethoprim.
• the antimalarial drug pyrimethamine.
• the experimental new antimalarial drug JPC-2056, which also works much better against toxoplasmosis.
• the chemotherapeutic agents methotrexate, raltitrexed and pemetrexed. Methotrexate, the first anticancer drug, acts on this enzyme binding to it some 1000 times more tightly than folate itself.

Deficiency of the enzyme may be a cause of folate deficiency, and therefore of megaloblastic anemia. Treatment is with reduced forms of folic acid.

References

Further reading

External links

• 1988 Nobel lecture in Medicine