DNA polymerase, ribonucleotide reductase, and DNA primase

DNA polymerase, ribonucleotide reductase (RNR), and DNA primase are essential enzymes that coordinately regulate DNA replication and repair. Ribonucleotide reductase catalyzes the conversion of ribonucleoside diphosphates into deoxyribonucleoside diphosphates, providing the necessary building blocks for DNA synthesis (UniProt: P23921). DNA primase initiates replication by synthesizing short RNA primers, which are then extended by DNA polymerase to form new DNA strands (UniProt: P09884). These enzymes are critical therapeutic targets in oncology, particularly for antimetabolite drugs like clofarabine and gemcitabine. These drugs often act as multi-target inhibitors; for instance, clofarabine inhibits RNR to deplete nucleotide pools while simultaneously inhibiting DNA polymerase to terminate chain elongation (PubMed: 16428498). This combined inhibition leads to S-phase cell cycle arrest and apoptosis, making these enzymes vital for treating various leukemias and solid tumors (StatPearls: NBK554540). Beyond oncology, inhibitors of these enzymes are also explored for antiviral and antibacterial applications due to their fundamental role in microbial genome replication.

Other names

DNA replication machineryNucleoside analog targetsDNA synthesis enzymesDNA-directed DNA polymeraseRibonucleoside-diphosphate reductaseDNA-directed RNA polymerase

Inhibition of deoxyribonucleotide synthesis via ribonucleotide reductase and direct inhibition of DNA polymerase and primase activity to halt DNA strand elongation.