Ribonucleoside-diphosphate reductase (RNR) (RNR)

Human ribonucleotide reductase (RNR) is a vital enzyme complex responsible for the de novo conversion of ribonucleoside diphosphates into deoxyribonucleoside diphosphates, providing the necessary precursors for DNA synthesis and repair [Annual Review of Biochemistry, 2006; Current Medicinal Chemistry, 2005]. The enzyme is typically composed of a large catalytic subunit (RRM1) and a smaller regulatory subunit (RRM2 or RRM2B), which contains a stable tyrosyl radical essential for catalysis [Oncogene, 2015]. Due to its central role in maintaining the deoxyribonucleoside triphosphate (dNTP) pool, RNR activity is tightly regulated throughout the cell cycle and is significantly upregulated in many types of cancer to support rapid proliferation [Biochimica et Biophysica Acta, 2004]. Consequently, RNR has become a prominent target for anticancer therapy, with inhibitors designed to either quench the tyrosyl radical or act as substrate analogs [Cancer Biology & Therapy, 2006]. Clinical agents like hydroxyurea and gemcitabine exploit this vulnerability to induce S-phase arrest and apoptosis in malignant cells [Current Medicinal Chemistry, 2005; Journal of B.U.ON., 2012]. Beyond oncology, RNR inhibition is also explored in the treatment of certain viral infections and hematological disorders like sickle cell anemia [Annual Review of Biochemistry, 2006; New England Journal of Medicine, 2003]. Therapeutic challenges include the development of drug resistance through subunit overexpression and the potential for systemic toxicities such as myelosuppression [Oncogene, 2015; Cancer Biology & Therapy, 2006]. Ongoing research focuses on developing next-generation inhibitors with higher specificity for the RRM2 subunit to improve efficacy and safety profiles [Biochimica et Biophysica Acta, 2004].

Other names

Ribonucleotide reductaseRibonucleotide diphosphate reductaseRRRRM1/RRM2 complexRibonucleoside-diphosphate reductase holoenzyme

Inhibition of ribonucleotide reductase prevents the conversion of ribonucleoside diphosphates to deoxyribonucleoside diphosphates, leading to the depletion of intracellular dNTP pools. This depletion inhibits DNA polymerase activity, halts DNA replication and repair, induces S-phase cell cycle arrest, and ultimately triggers apoptosis in rapidly dividing cells.