Ribonucleotide reductase class I (RNR)

Ribonucleotide reductase (RNR) is the rate-limiting enzyme responsible for the de novo synthesis of deoxyribonucleotides (dNTPs) from ribonucleotides, providing the essential building blocks for DNA replication and repair. In humans, the Class I RNR exists as heterotetrameric complexes consisting of a large catalytic subunit (RRM1, or α) and one of two small regulatory subunits: RRM2 (β), which is primarily expressed during the S-phase for nuclear DNA replication, or RRM2B (p53R2, or β′), which is induced by p53 and hypoxia to support DNA repair and mitochondrial DNA maintenance. The enzyme utilizes a unique radical-based mechanism involving a di-iron center and a stable tyrosyl radical to initiate catalysis. Due to its critical role in cell proliferation, RNR is a well-established target in oncology, with inhibitors like hydroxyurea and various nucleoside analogs used to deplete dNTP pools and induce cell cycle arrest. Beyond cancer, RNR is also a target for antiviral and antibacterial agents, and mutations in its subunits are linked to severe metabolic disorders such as mitochondrial DNA depletion syndrome.

Other names

Ribonucleoside-diphosphate reductaseRRM1/RRM2 complexRRM1/RRM2B complexp53R2 complexR1/R2 complexR1/R2B complex

Inhibition of enzyme activity through scavenging of the tyrosyl radical, competitive inhibition of the catalytic site by nucleoside triphosphates, or chelation of the essential iron cofactor.