Ribonucleoside-diphosphate reductase and DNA-directed DNA polymerase (RNR / DNA Pol)

Ribonucleotide reductase (RNR) and DNA polymerase are essential enzymes for DNA replication and repair, serving as the primary molecular targets for the chemotherapeutic agent gemcitabine (StatPearls: Gemcitabine, 2023). RNR is responsible for the de novo synthesis of deoxyribonucleotides (dNTPs) by reducing ribonucleoside diphosphates, a rate-limiting step in DNA production (UniProt P23921). DNA polymerases utilize these dNTPs to synthesize new DNA strands during the S-phase of the cell cycle. Gemcitabine, a nucleoside analog, acts as a prodrug that is intracellularly phosphorylated into active metabolites. Its diphosphate form (dFdCDP) potently inhibits RNR, which depletes the pool of natural nucleotides, while its triphosphate form (dFdCTP) competes with dCTP for incorporation into DNA by DNA polymerase (PubChem CID 60750). This incorporation leads to masked chain termination, where the DNA strand is terminated after the addition of one more nucleotide, effectively hiding the analog from proofreading enzymes and leading to cell death (NIH/NCI).

Other names

Ribonucleotide reductaseDNA polymeraseRibonucleoside-diphosphate reductaseDNA-directed DNA polymeraseRNRDNA PolRRM1RRM2

Gemcitabine diphosphate inhibits ribonucleotide reductase to deplete dNTP pools, while gemcitabine triphosphate is incorporated into DNA by DNA polymerase, leading to masked chain termination.