Ribonucleotide reductase (RNR) (RNR)

Ribonucleotide reductase (RNR) is a critical enzyme that catalyzes the rate-limiting step in the de novo synthesis of deoxyribonucleotides (dNTPs) by reducing their corresponding ribonucleotides. This process provides the essential building blocks required for DNA replication and repair, making RNR fundamental to genomic stability and cell proliferation across all living organisms. The enzyme is a multi-subunit complex, typically consisting of a large catalytic subunit (RRM1) and a small radical-generating subunit (RRM2 or p53R2), whose expression peaks during the S-phase of the cell cycle. Because rapid cell division in cancer requires a continuous supply of dNTPs, RNR is frequently overexpressed in malignancies such as pancreatic cancer, leukemia, and lung cancer, establishing it as a prominent target for chemotherapy. Drugs targeting RNR include antimetabolites like gemcitabine, which inhibit the catalytic subunit, and radical scavengers like hydroxyurea, which disrupt the small subunit's activity. Therapeutic challenges include the emergence of drug resistance due to subunit upregulation and significant safety concerns like myelosuppression, reflecting the enzyme's necessity in normal hematopoietic cell division.

Other names

Ribonucleoside-diphosphate reductaseRibonucleoside-triphosphate reductaseRibonucleotide ReductaseRRRNR enzyme complex

Direct inhibition of the catalytic site (C-site) as suicide substrates, allosteric inhibition at Activity (A) or Specificity (S) sites, quenching of the essential tyrosyl free radical, iron chelation to disrupt the binuclear iron center, or prevention of RRM1-RRM2 subunit association.