Biochemistry · Enzyme
Dihydrofolate reductase (DHFR) !
DHFR turns dihydrofolate back into tetrahydrofolate, the carrier of one-carbon units for DNA building blocks. Methotrexate blocks it.
Updated 2026-11-01
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Key facts
- 7,8-dihydrofolate + NADPH + H⁺ → tetrahydrofolate + NADP⁺.
- Tetrahydrofolate carries one-carbon units to make purines, thymidylate (dTMP) and glycine.
- Every dTMP made by thymidylate synthase leaves a dihydrofolate behind: DHFR regenerates the folate pool.
- Dietary folic acid is also reduced by this enzyme on its way to the active form.
Structure
- A small protein of 187 amino acids that holds NADPH and the folate together in its active site.
- Structure 1U72 is a human DHFR ternary complex with NADPH and methotrexate, from a study of resistance variants.
Regulation
- It binds its own mRNA, a way of tuning how much enzyme is made.
- In the S and G2/M phases it moves to the nucleus and to replication forks, with thymidylate synthase and SHMT1.
Inhibitors and toxins
- Methotrexate: a folate analogue that fills the active site.
Clinical notes
- Rapidly dividing tissues (tumour cells, bone marrow, gut lining) are the most sensitive: hence its use against cancer and its marrow and mouth toxicity.
- At lower amounts it treats rheumatoid arthritis and severe psoriasis, where its exact mechanism is not fully known.
- Folic or folinic acid (leucovorin) reduces adverse effects; leucovorin is given in overdose because it bypasses the block.
- Inherited DHFR deficiency is rare: megaloblastic anemia and cerebral folate deficiency.
Drugs that act here
Related conditions
Related
Test yourself
Think of the answer, then tap the question to see it.
Which reaction does DHFR catalyse?
Dihydrofolate + NADPH → tetrahydrofolate + NADP⁺.
Why is DHFR needed for dTMP synthesis?
Thymidylate synthase turns methylene-THF into dihydrofolate; DHFR must regenerate tetrahydrofolate.
Why does leucovorin protect against methotrexate toxicity?
It is a reduced folate that enters the pool beyond the DHFR step, so cells no longer need the blocked enzyme.
Which tissues are hurt first by DHFR inhibition?
Fast-dividing ones: bone marrow, gut and mouth lining, and tumour cells.
Educational information, not medical advice. For any symptom, see a health professional.
Sources: DHFR: Dihydrofolate reductase (human) (UniProt, 2026); 1U72: Understanding the Role of Leu22 Variants in Methotrexate Resistance: Comparison of Wild-type and Leu22Arg Variant Mouse and Human Dihydrfolate Reductase Ternary Crystal Complexes with Methotrexate and NADPH (RCSB Protein Data Bank, 2026); METHOTREXATE tablet (DailyMed, US National Library of Medicine, 2026); Methotrexate: MedlinePlus Drug Information (MedlinePlus, US National Library of Medicine, 2026).
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Representative model, for educational purposes only.