Section snippets
Cell cycle, signaling, and nucleotide metabolism
Nucleotides are the fundamental building blocks for the preservation of life. As monomeric units, purine and pyrimidine nucleotides are polymerized into RNA and DNA. Mammalian cells require extracellular growth factor-initiated signals to leave the quiescent state and enter the cell cycle. Once in S phase, cells use ribonucleotide reductase (RNR) to promote deoxynucleoside triphosphate (dNTP) synthesis by converting nucleoside triphosphate (NTP) into dNTP [1]. However, further research is
Nucleotide metabolism
Cells use two metabolic routes to generate nucleotides: the de novo and nucleotide salvage pathways. The de novo nucleotide pathways assemble the purine and pyrimidine rings using precursors, such as amino acids, activated sugar, ATP, and bicarbonate. By contrast, the salvage pathway uses intermediate metabolites (nucleobases and nucleosides) derived from nucleotide catabolism or the surrounding environment to maintain cellular nucleotide pools [8,12]. Although several studies have implicated
Metabolism of pyrimidine nucleotides
De novo biosynthesis of pyrimidine nucleotide is catalyzed by three gene products: carbamoyl-phosphate synthetase 2 (CPS2), aspartate transcarbamoylase (ATC), and dihydroorotase (DHO) (CAD), dihydroorotate dehydrogenase (DHODH), and uridine monophosphate synthetase (UMPS) [17]. Pyrimidine nucleotides are essential for nucleic acid synthesis in all organisms with different temporal and/or spatial roles in cellular metabolism [18]. Proliferating cells activate the de novo pyrimidine pathway,
Metabolism of purine nucleotides
One of the significant differences between de novo pyrimidine and purine synthesis lies in the integration of the activated ribose (phosphoribosyl diphosphate; PRPP) to the nucleobase ring. The de novo purine synthesis pathway starts with PRPP. It requires the coordinated actions of six enzymes to catalyze ten sequential reactions to synthesize the first purine nucleotide inosine 5′-monophosphate (IMP) from PRPP. By contrast, the pyrimidine ring is first synthesized before incorporating PRPP at
Signaling and transcriptional control of the de novo nucleotide synthesis pathways
The RAS-extracellular signal-regulated kinase (ERK), phosphatidylinositol 3-kinase (PI3K)-mTORC1, and Hippo-YAP signaling pathways are cell master regulators that control cell growth, proliferation, motility, differentiation, survival, and metabolism in response to extracellular cues. The metabolic effects can be mediated through post-translational, translational, post-transcriptional, or transcriptional mechanisms (Table 1). Herein, we review the current understanding of the connections
mTORC1 and pyrimidine synthesis
mTORC1 signaling is regulated by hormones, growth factors, amino acids, purines, cytokines, oncogenes, and tumor suppressors [25]. It promotes the production of new nucleotides to facilitate an increased demand for RNA and DNA synthesis [26,27]. The PI3K/AKT/mTORC1 pathway is physiologically stimulated by growth factors and hormonal signals, such as insulin and insulin-like growth factor 1 (IGF1). In proliferating cells, activation of this pathway promotes an increase in pyrimidine synthesis
mTORC1 and purine synthesis
Compared with the regulation of de novo pyrimidine synthesis, mTORC1 signaling stimulates de novo purine synthesis through long term-mediating mechanisms via the induction of the transcription factors activating transcription factor 4 (ATF4; Figure 2A) and MYC, which both control the expression of specific metabolic enzymes contributing to, or directly required for, de novo purine synthesis. For example, in response to mTORC1 activation, ATF4 enhances the production of enzymes that belong to
Indirect regulation of de novo nucleotide synthesis by the Hippo-Yap pathway
Besides mTORC1 and ERK signaling, Hippo-Yap signaling is an evolutionarily conserved pathway that significantly controls tissue growth and organ size in response to different stimuli [50]. Through the induction of glutamine synthetase/glutamate-ammonia ligase (GLUL), Yap1 was recently shown to increase cellular glutamine levels and subsequently enhance de novo nucleotide synthesis in zebrafish [51]. Furthermore, pharmacological inhibition of GLUL sensitized Yap1-driven liver tumors to
Glucose metabolism
The glycolytic enzyme pyruvate kinase M2 (PKM2), which phosphorylates ADP to ATP and mediates pyruvate synthesis from phosphoenolpyruvate, controls the glycolysis rate and enables the shunt of glycolytic intermediates upstream of phosphoenolpyruvate into the PPP and serine/glycine synthesis pathway. This shunt enhances the production of substrates [ribose 5-phosphate, NADPH (from PPP), glycine (from the serine biosynthesis pathway), and one-carbon units (from the tetrahydrofolate pathway)] for
Targeting nucleotide synthesis as a therapeutic avenue to fight cancer and immune diseases
Cancer cells and cells infected with viruses undergo significant changes in nucleotide metabolism, which enable them to survive and multiply. Nucleotide synthesis provides cancer cells and viruses with building blocks to proliferate and evade the immune system, making it a target for therapeutic strategies in both diseases [6,11]. While previous studies have discussed various therapeutic approaches for targeting nucleotide metabolism in different disorders [1,6,8,11,21,71., 72., 73.], here we
Concluding remarks
Cancer, viral-infected, or immune cells exploit the metabolism of nucleotides to overcome the challenges they face during abnormal growth and proliferation. Several signaling pathways regulate nucleotide synthesis in cells, but our understanding of the intricate regulatory network impinging on nucleotide synthesis pathways under normal and pathological states is still emerging. Inhibiting the catalytic activity of the nucleotide metabolic enzymes with small molecules is a potential therapeutic
Acknowledgments
We apologize to our colleagues whose work we were not able to cover in this review due to space constraints. We thank Hina Anjum for contributing to figure preparation. This work was supported by grants from the National Institutes of Health [R01GM135587 and R01GM143334 (I.B-S.)], and by a LAM Foundation Established Investigator Award (LAM0151E01-22; I.B-S.).
Declaration of interests
The authors declare no competing interests.
Glossary
- Anti-PD1 therapy
- novel immunotherapy aims not to kill cancer cells directly but to block a pathway that shields cancer cells from the immune system.
- De novo nucleotide synthesis pathways
- metabolic pathways that assemble purine or pyrimidine nucleotide rings from simple precursors, such as amino acids, activated ribose, ATP, and bicarbonate. Rapidly dividing cells activate the de novo nucleotide synthesis pathways for their growth and proliferation.
- Gluconeogenesis
- metabolic pathway that generates
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