Balancing de novo and salvage pathways in cellular nucleotide synthesis

Nucleotides are essential for DNA replication, repair and transcription and are supplied through two principal pathways, salvage and de novo synthesis. While the core enzymes underlying these pathways have long been characterized, recent work has uncovered mechanisms that regulate pathway choice across cell states. This Review summarizes our current understanding of how cells govern the balance between salvage and de novo synthesis of nucleotides. We examine context-dependent pathway utilization across organisms, tissues and physiological contexts, and discuss the molecular determinants of pathway choice, including precursor availability, cellular demand, transcriptional programmes, mitochondrial and one-carbon metabolism, post-translational regulation and multienzyme organization. We further explore how disruption of this balance shapes human disease and consider the translational potential of nucleotide metabolic plasticity. Finally, we highlight emerging technologies for resolving tissue-specific and cell-type-specific pathway utilization and outline outstanding questions in pathway regulation and therapeutic targeting. Collectively, this Review summarizes current knowledge of how cells dynamically balance de novo synthesis and salvage and highlights opportunities to therapeutically target nucleotide metabolic dependencies.