De novo and salvage purine synthesis pathways across tissues and tumors.

Purine nucleotides are vital for RNA and DNA synthesis, signaling, metabolism, and energy homeostasis. To synthesize purines, cells use two principal routes: the de novo and salvage pathways. Traditionally, it is believed that proliferating cells predominantly rely on de novo synthesis, whereas differentiated tissues favor the salvage pathway. Unexpectedly, we find that adenine and inosine are the most effective circulating precursors for supplying purine nucleotides to tissues and tumors, while hypoxanthine is rapidly catabolized and poorly salvaged in vivo. Quantitative metabolic analysis demonstrates comparative contribution from de novo synthesis and salvage pathways in maintaining purine nucleotide pools in tumors. Notably, feeding mice nucleotides accelerates tumor growth, while inhibiting purine salvage slows down tumor progression, revealing a crucial role of the salvage pathway in tumor metabolism. These findings provide fundamental insights into how normal tissues and tumors maintain purine nucleotides and highlight the significance of purine salvage in cancer. [Display omitted] • The small intestine has high de novo synthesis, while kidney shows high purine salvage • The de novo synthesis and salvage pathway contribute similarly to tumor purine pools • The purine salvage pathway plays a crucial role in promoting tumor growth • Dietary supplementation of nucleotides accelerates tumor growth Comprehensive isotope tracing analyses reveal the contribution of de novo synthesis and salvage pathways in supplying purine nucleotides across major tissues and tumors. [ABSTRACT FROM AUTHOR]