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[Biochemistry](https://durgical.com/en/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.

**EC number**
[1.5.1.3](https://www.enzyme-database.org/query.php?ec=1.5.1.3)

**Genes**
DHFR

**Structure (PDB)**
[1U72](https://www.rcsb.org/structure/1U72)

## 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

- [Methotrexate](https://durgical.com/en/pharmacology/methotrexate/)
- [Folic acid](https://durgical.com/en/pharmacology/folic-acid/)

## Related conditions

- [Rheumatoid arthritis](https://durgical.com/en/conditions/rheumatoid-arthritis/)
- [Molar pregnancy (hydatidiform mole)](https://durgical.com/en/conditions/molar-pregnancy/)

## Related

- [Thymidylate synthase](https://durgical.com/en/biochemistry/enzymes/thymidylate-synthase/)

## 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.

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Educational information, not medical advice. For any symptom, see a health professional.

Sources: [DHFR: Dihydrofolate reductase (human)](https://rest.uniprot.org/uniprotkb/P00374.txt) (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](https://www.rcsb.org/structure/1U72) (RCSB Protein Data Bank, 2026); [METHOTREXATE tablet](https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=aafd97c1-3a0a-42b2-845a-a9db9bb7d876) (DailyMed, US National Library of Medicine, 2026); [Methotrexate: MedlinePlus Drug Information](https://medlineplus.gov/druginfo/meds/a682019.html) (MedlinePlus, US National Library of Medicine, 2026).

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Representative model, for educational purposes only.

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Source: https://durgical.com/en/biochemistry/enzymes/dihydrofolate-reductase/
License: CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). Cite as: DurgiPedia (durgical.com), https://durgical.com/en/biochemistry/enzymes/dihydrofolate-reductase/