Prodrug activation enzymes and nucleotide pools

The term Prodrug activation enzymes and nucleotide pools refers to the integrated biochemical network responsible for the intracellular conversion of nucleoside and nucleotide analogs into their pharmacologically active forms. This process typically involves a cascade of phosphorylation events mediated by cellular kinases such as deoxycytidine kinase (DCK), thymidine kinase (TK1/TK2), and adenosine kinase (ADK) (Jordheim et al., 2013). The therapeutic efficacy of these agents is critically dependent on the competition between the resulting active drug triphosphates and the endogenous nucleotide pools, which are regulated by enzymes like ribonucleotide reductase (RRM) (Galmarini et al., 2002). In the context of cancer and viral infections, these pathways are exploited to disrupt nucleic acid synthesis, thereby inducing cell death in malignant cells or halting viral replication (Zhang et al., 2021). However, the clinical utility of these drugs is often limited by imbalances in nucleotide pools or mutations in activating enzymes, which serve as primary mechanisms of drug resistance and contribute to significant toxicities such as myelosuppression (Sabit et al., 2016).

Other names

Nucleoside metabolism pathwayNucleotide salvage pathwayAntimetabolite activation systemNucleoside analog metabolism

Intracellular enzymes (e.g., kinases) phosphorylate nucleoside/nucleotide analogs into active triphosphate forms, which then compete with endogenous nucleotide pools for incorporation into DNA or RNA by polymerases, leading to chain termination or apoptosis.