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[Biochemistry](https://durgical.com/en/biochemistry/) · Enzyme

# Ribonucleotide reductase

Turns ribonucleotides into deoxyribonucleotides, the building blocks of DNA; it is the target of hydroxyurea.

Updated 2026-11-01

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## Key facts

- NDP → dNDP (ADP, GDP, CDP, UDP): removes the 2'-OH of the ribose. It is the only de novo source of deoxyribonucleotides.
- Two subunits: R1 (RRM1, catalytic and allosteric sites) and R2 (RRM2, tyrosyl radical with iron).
- Electrons come from NADPH via thioredoxin and thioredoxin reductase.
- Activity site: ATP turns it on, dATP turns it off. Specificity site: the bound dNTP decides which substrate is reduced.

**Also called**
RNR

**EC number**
[1.17.4.1](https://www.enzyme-database.org/query.php?ec=1.17.4.1)

**Genes**
RRM1, RRM2, RRM2B

**Structure (PDB)**
[3HND](https://www.rcsb.org/structure/3HND)

## Regulation

- dATP at the activity site: global inhibition.
- Specificity: ATP/dATP → reduces CDP and UDP; dTTP → reduces GDP; dGTP → reduces ADP. This keeps the four dNTPs balanced.
- R2 is expressed in S phase; the p53R2 variant (RRM2B) supplies dNTPs to mitochondria.

## Inhibitors and toxins

- Hydroxyurea (quenches the tyrosyl radical)
- Gemcitabine diphosphate
- Cladribine and fludarabine (as triphosphates)

## Clinical notes

- Hydroxyurea is used in sickle cell disease (it raises fetal haemoglobin) and in myeloproliferative neoplasms.
- In ADA deficiency, accumulated dATP inhibits it and stops lymphocytes from dividing.
- RRM2B variants cause mitochondrial DNA depletion syndromes.

## Pathways

- [Pyrimidine synthesis](https://durgical.com/en/biochemistry/pathways/pyrimidine-synthesis/)

## Related conditions

- [Adenosine deaminase deficiency (ADA-SCID)](https://durgical.com/en/conditions/adenosine-deaminase-deficiency/)

## Related

- [Adenosine deaminase (ADA)](https://durgical.com/en/biochemistry/enzymes/adenosine-deaminase/)
- [Thymidylate synthase](https://durgical.com/en/biochemistry/enzymes/thymidylate-synthase/)
- [dTMP (thymidine monophosphate)](https://durgical.com/en/biochemistry/molecules/dtmp/)
- [Drugs acting on nucleotide metabolism](https://durgical.com/en/biochemistry/topics/drugs-acting-on-nucleotide-metabolism/)
- [Nucleotide structure](https://durgical.com/en/biochemistry/topics/nucleotide-structure/)

## Test yourself

Think of the answer, then tap the question to see it.

## On which nucleotide form does ribonucleotide reductase act?

On diphosphates (NDPs): ADP, GDP, CDP and UDP become dADP, dGDP, dCDP and dUDP.

## How does hydroxyurea inhibit ribonucleotide reductase?

It destroys the tyrosyl radical of the R2 subunit, which catalysis requires.

## What effect does dATP have on ribonucleotide reductase?

Bound to the activity site it switches the enzyme off; its build-up in ADA deficiency therefore blocks DNA synthesis.

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

Sources: [RRM1: Ribonucleoside-diphosphate reductase large subunit (human)](https://www.uniprot.org/uniprotkb/P23921/entry) (UniProt, 2026); [RRM2: Ribonucleoside-diphosphate reductase subunit M2 (human)](https://www.uniprot.org/uniprotkb/P31350/entry) (UniProt, 2026); [3HND: Crystal structure of human ribonucleotide reductase 1 bound to the effector TTP and substrate GDP](https://www.rcsb.org/structure/3HND) (RCSB Protein Data Bank, 2026); [Hydroxyurea: MedlinePlus Drug Information](https://medlineplus.gov/druginfo/meds/a682004.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/ribonucleotide-reductase/
License: CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). Cite as: DurgiPedia (durgical.com), https://durgical.com/en/biochemistry/enzymes/ribonucleotide-reductase/