Ribonucleotide reductase (RNR) complex (RNR)

Ribonucleotide reductase (RNR) is a critical enzyme complex responsible for the de novo conversion of ribonucleoside diphosphates (NDPs) into deoxyribonucleoside diphosphates (dNDPs), which are the essential precursors for DNA synthesis and repair (NIH, 2020; MDPI, 2023). In humans, the class I RNR holoenzyme typically functions as a heterotetramer composed of two large catalytic subunits (RRM1) and two small regulatory subunits (RRM2 or RRM2B) (NIH, 2018; MDPI, 2023). RRM1 contains the catalytic site and allosteric regulation sites, while RRM2 provides a stable tyrosyl radical and a di-iron center necessary for the initiation of catalysis (NIH, 2022; MDPI, 2023). Because RNR activity is the rate-limiting step in dNTP production, it is highly regulated throughout the cell cycle, with RRM2 expression peaking during the S-phase to support rapid DNA replication (NIH, 1984; NIH, 2020). In many cancers, RNR subunits are overexpressed, leading to expanded dNTP pools that facilitate uncontrolled cell proliferation, genomic instability, and resistance to chemotherapy (NIH, 2021; AACR, 2013). Consequently, RNR is a well-established therapeutic target; drugs like hydroxyurea act as radical scavengers, while nucleoside analogs such as gemcitabine and clofarabine inhibit the enzyme to deplete dNTPs and induce apoptosis (NIH, 2006; NIH, 2018).

Other names

Ribonucleoside-diphosphate reductaseR1/R2 complexRibonucleotide reductase M1/M2 complexClass I ribonucleotide reductaseRR

Inhibition of de novo deoxyribonucleotide synthesis through free-radical scavenging of the tyrosyl radical, iron chelation of the di-iron center, competitive inhibition of the catalytic site by nucleoside triphosphates, or disruption of the RRM1-RRM2 subunit interaction.