Balancing de novo and salvage pathways in cellular nucleotide synthesis.

Cells dynamically balance salvage and de novo nucleotide synthesis across physiological states, with pathway choice shaped by precursor supply, demand, and regulatory programs rather than fixed enzyme presence.

• Why it matters: Nucleotide availability must match DNA replication, repair, and transcription needs, yet how cells switch between salvage and de novo routes across contexts remains incompletely understood.
• What they did: This Review synthesizes recent findings on context-dependent pathway utilization across organisms, tissues, and physiological settings, focusing on determinants such as precursor availability, transcriptional programs, mitochondrial and one-carbon metabolism, post-translational regulation, and multienzyme organization.
• The result: Disrupting this balance is linked to human disease, and the authors outline how nucleotide metabolic plasticity and emerging tissue- and cell-type-resolved technologies could inform therapeutic targeting.

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