Ribonucleoside-diphosphate reductase subunit M1 (RRM1)

Ribonucleoside-diphosphate reductase subunit M1 (RRM1) is the large catalytic subunit of the ribonucleotide reductase (RNR) enzyme complex, which catalyzes the rate-limiting step in the de novo synthesis of deoxyribonucleotides (dNTPs) by converting ribonucleoside diphosphates into their deoxy forms. This process is essential for providing the building blocks necessary for DNA replication and repair, making RRM1 a critical regulator of the cell cycle, particularly during the S-phase. In many malignancies, RRM1 is overexpressed to support the high demand for dNTPs in rapidly proliferating cancer cells, which has established it as a major therapeutic target in oncology. Chemotherapeutic agents such as gemcitabine and clofarabine target RRM1 by acting as mechanism-based inhibitors that irreversibly bind to the enzyme, leading to dNTP pool depletion and subsequent apoptosis. Furthermore, RRM1 expression levels serve as a significant clinical biomarker, as high levels are frequently associated with resistance to gemcitabine-based therapies and poor prognosis in various cancers.

Other names

Ribonucleotide reductase catalytic subunit M1Ribonucleotide reductase large subunitR1RR1Ribonucleoside-diphosphate reductase large subunit

Nucleoside analogs are phosphorylated to their active diphosphate forms, which act as mechanism-based inhibitors (suicide substrates) that bind to the catalytic site of the R1 subunit, causing irreversible inactivation of the enzyme and depletion of the deoxyribonucleotide (dNTP) pool required for DNA synthesis.