Purine Metabolism and Biosynthesis in Cancer Systems

Purines are nitrogenous bases that constitute fundamental building blocks of DNA and RNA. Through two primary routes—de novo synthesis and salvage pathways—cells maintain purine pools required for nucleic acid production, energy transfer, signal transduction and glycosylation. Cancer cells, driven by dysregulated oncogenes and suppressed tumour suppressors, reprogramme these pathways to fuel rapid proliferation and survival. In the de novo route, a sequence of enzymatic steps converts phosphoribosyl pyrophosphate (PRPP) into inosine monophosphate (IMP), the precursor for adenosine and guanosine nucleotides. These enzymes often assemble into multienzyme complexes termed purinosomes, enabling efficient channeling of intermediates. Oncogenic signals such as hyperactivation of MYC, RAS and mTOR pathways stimulate transcriptional and post-translational control of key biosynthetic enzymes, while alterations to the salvage pathway and adenosine monophosphate-activated protein kinase (AMPK) further fine-tune nucleotide homeostasis under metabolic stress. Aberrant purine metabolism supports not only DNA and RNA synthesis but also generates signalling nucleotides like cyclic guanosine monophosphate (cGMP), which may enhance stemness and metastatic potential. Therapeutic interventions targeting rate-limiting enzymes—such as IMP dehydrogenase (IMPDH) and amidophosphoribosyltransferase (PPAT)—or disrupting purinosome assembly offer promising avenues to selectively impair cancer cell proliferation and overcome resistance to conventional treatments.

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Purine Metabolism and Biosynthesis in Cancer Systems publication trend

The graph below shows the total number of articles in purine metabolism and biosynthesis in cancer systems across all publications each year (not limited to Nature Index journals).

Technical terms

De novo purine biosynthesis: Multi-step enzymatic pathway converting phosphoribosyl pyrophosphate into inosine monophosphate to generate purine nucleotides.

Salvage pathway: Enzymatic process recycling free purine bases and nucleosides back into nucleotide pools, reducing biosynthetic demand.

Purinosome: Dynamic multienzyme complex that organises de novo purine biosynthesis enzymes for efficient substrate channeling.

Inosine monophosphate dehydrogenase (IMPDH): Rate-limiting enzyme converting IMP to xanthosine monophosphate en route to guanine nucleotides.

Cyclic guanosine monophosphate (cGMP): Second messenger derived from GTP that activates protein kinases influencing cell proliferation and migration.

References

1. Regulation of mammalian nucleotide metabolism and biosynthesis. Nucleic Acids Research (2015).
2. Quantitative Analysis of Purine Nucleotides Indicates That Purinosomes Increase de Novo Purine Biosynthesis* ♦. Journal of Biological Chemistry (2015).
3. Cancer Cells Tune the Signaling Pathways to Empower de Novo Synthesis of Nucleotides. Cancers (2019).
4. Nucleotide de novo synthesis increases breast cancer stemness and metastasis via cGMP-PKG-MAPK signaling pathway. PLOS Biology (2020).
5. Targeting nucleotide metabolism: a promising approach to enhance cancer immunotherapy. Journal of Hematology & Oncology (2022).