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.
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
Related conditions
Related
- Adenosine deaminase (ADA)
- Thymidylate synthase
- dTMP (thymidine monophosphate)
- Drugs acting on nucleotide metabolism
- 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.
Educational information, not medical advice. For any symptom, see a health professional.
Sources: RRM1: Ribonucleoside-diphosphate reductase large subunit (human) (UniProt, 2026); RRM2: Ribonucleoside-diphosphate reductase subunit M2 (human) (UniProt, 2026); 3HND: Crystal structure of human ribonucleotide reductase 1 bound to the effector TTP and substrate GDP (RCSB Protein Data Bank, 2026); Hydroxyurea: MedlinePlus Drug Information (MedlinePlus, US National Library of Medicine, 2026).
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