Ribonucleotide-diphosphate reductase (RNR)

Ribonucleotide-diphosphate reductase (RNR) is an essential enzyme complex that catalyzes the rate-limiting step in the de novo synthesis of deoxyribonucleotides (dNTPs), which are the fundamental building blocks for DNA replication and repair [1, 4]. The enzyme converts ribonucleoside diphosphates (NDPs) into their corresponding deoxyribonucleoside diphosphates (dNDPs) through a sophisticated free-radical mechanism [4, 12]. In humans, RNR typically exists as a heterotetramer or higher-order oligomer consisting of a large catalytic subunit (RRM1) and a small regulatory subunit (RRM2 or RRM2B) [1, 9]. Because RNR activity is highly upregulated during the S-phase of the cell cycle to support rapid DNA synthesis, it is a critical target for anti-proliferative therapies, particularly in cancer [2, 13]. Clinically, RNR is targeted by several classes of drugs, including nucleoside analogs like gemcitabine and clofarabine, which inhibit the catalytic subunit, and radical scavengers like hydroxyurea, which target the regulatory subunit [1, 3]. Beyond its role in oncology, RNR is also a potential target for antibacterial and antiviral agents, as many pathogens rely on their own RNR enzymes for genome replication [10, 13]. However, therapeutic use of RNR inhibitors is often limited by systemic toxicities such as myelosuppression, reflecting the enzyme's vital role in normal hematopoiesis and DNA maintenance [3, 12].

Other names

Ribonucleoside-diphosphate reductaseRibonucleotide reductaseRRhRRRRM1/RRM2 complexRibonucleoside-diphosphate reductase large subunitRibonucleoside-diphosphate reductase small subunit

Ribonucleotide-diphosphate reductase (RNR) inhibitors primarily function by disrupting the de novo synthesis of deoxyribonucleotides (dNTPs) [1, 2]. Nucleoside analogs like gemcitabine and clofarabine are phosphorylated to their diphosphate forms, which then act as suicide inhibitors or competitive inhibitors of the R1 subunit (RRM1) [1, 12]. Non-nucleoside inhibitors, such as hydroxyurea and triapine, target the R2 subunit (RRM2) by scavenging the essential tyrosyl radical or chelating the iron center required for radical generation [1, 4]. These actions lead to the depletion of dNTP pools, causing replication stress, DNA damage, and ultimately apoptosis in rapidly proliferating cells [2, 12].