Regulation of nucleotide metabolism in cancers and immune disorders (2023)

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


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.).

(Video) Metabolism | Nucleotide Synthesis | Purine & Pyrimidine Synthesis

Declaration of interests

The authors declare no competing interests.


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.

metabolic pathway that generates

Recommended articles (6)

  • Research article

    Caveolae sense oxidative stress through membrane lipid peroxidation and cytosolic release of CAVIN1 to regulate NRF2

    Developmental Cell, Volume 58, Issue 5, 2023, pp. 376-397.e4

    (Video) 35. Nucleotide Metabolism 2

    Caveolae have been linked to many biological functions, but their precise roles are unclear. Using quantitative whole-cell proteomics of genome-edited cells, we show that the oxidative stress response is the major pathway dysregulated in cells lacking the key caveola structural protein, CAVIN1. CAVIN1 deletion compromised sensitivity to oxidative stress in cultured cells and in animals. Wound-induced accumulation of reactive oxygen species and apoptosis were suppressed in Cavin1-null zebrafish, negatively affecting regeneration. Oxidative stress triggered lipid peroxidation and induced caveolar disassembly. The resulting release of CAVIN1 from caveolae allowed direct interaction between CAVIN1 and NRF2, a key regulator of the antioxidant response, facilitating NRF2 degradation. CAVIN1-null cells with impaired negative regulation of NRF2 showed resistance to lipid-peroxidation-induced ferroptosis. Thus, caveolae, via lipid peroxidation and CAVIN1 release, maintain cellular susceptibility to oxidative-stress-induced cell death, demonstrating a crucial role for this organelle in cellular homeostasis and wound response.

  • Sinturel et al. demonstrate that feeding–fasting rhythms and light–dark cycles direct daily changes in liver mass and cell size. These feeding–fasting- and light–dark-driven diurnal fluctuations are controlled by an unconventional mechanism that affects ribosome assembly and protein levels during the active phase.

  • Research article

    Emerging metabolomic tools to study cancer metastasis

    Trends in Cancer, Volume 8, Issue 12, 2022, pp. 988-1001

    (Video) Nucleotide Metabolism II

    Metastasis is responsible for 90% of deaths in patients with cancer. Understanding the role of metabolism during metastasis has been limited by the development of robust and sensitive technologies that capture metabolic processes in metastasizing cancer cells. We discuss the current technologies available to study (i) metabolism in primary and metastatic cancer cells and (ii) metabolic interactions between cancer cells and the tumor microenvironment (TME) at different stages of the metastatic cascade. We identify advantages and disadvantages of each method and discuss how these tools and technologies will further improve our understanding of metastasis. Studies investigating the complex metabolic rewiring of different cells using state-of-the-art metabolomic technologies have the potential to reveal novel biological processes and therapeutic interventions for human cancers.

  • Research article

    Suppression of p16 Induces mTORC1-Mediated Nucleotide Metabolic Reprogramming

    Cell Reports, Volume 28, Issue 8, 2019, pp. 1971-1980.e8

    Reprogrammed metabolism and cell cycle dysregulation are two cancer hallmarks. p16 is a cell cycle inhibitor and tumor suppressor that is upregulated during oncogene-induced senescence (OIS). Loss of p16 allows for uninhibited cell cycle progression, bypass of OIS, and tumorigenesis. Whether p16 loss affects pro-tumorigenic metabolism is unclear. We report that suppression of p16 plays a central role in reprogramming metabolism by increasing nucleotide synthesis. This occurs by activation ofmTORC1 signaling, which directly mediates increased translation of the mRNA encoding ribose-5-phosphate isomerase A (RPIA), a pentose phosphate pathway enzyme. p16 loss correlates with activation of the mTORC1-RPIA axis in multiple cancer types. Suppression of RPIA inhibits proliferation only in p16-low cells by inducing senescence both invitro and invivo. These data reveal the molecular basis whereby p16 loss modulates pro-tumorigenic metabolism through mTORC1-mediated upregulation of nucleotide synthesis and reveals a metabolic vulnerability of p16-null cancer cells.

  • Research article

    (Video) Lippincotts Biochemistry Review (Chapter 22) Nucleotide metabolism || Study This!

    Single nucleotide polymorphisms of the NF-κB and STAT3 signaling pathway genes predict lung cancer prognosis in a Chinese Han population

    Cancer Genetics, Volume 208, Issue 6, 2015, pp. 310-318

    Inflammation contributes to human carcinogenesis and cancer progression. This study selected and analyzed single nucleotide polymorphisms (SNPs) of the NF-κB and STAT3 signaling pathway genes for associations with prognosis in 1,165 lung cancer patients from a Chinese Han population. The data showed that eight SNPs (i.e., rs10836, rs3732131, rs3732133, rs4072391, rs2273650, rs1053023, rs3744483, and rs28372683) can be grouped into low-, medium-, and high-risk genotypes based on survival data. The median overall survival time (MST) of this cohort of patients was 24.6months, whereas the MST of patients with low-risk genotypes reached 79.7months; MST of patients with the medium-risk genotypes was 25.5months, and those with high-risk genotypes was 22.7months. Overall survival was statistically different for sex (P=0.004), age (P=0.010), histological types (P=0.035), tumor stage (P<0.001), tumor size (P<0.001), surgery (P<0.001), chemoradiotherapy (P=0.007), and Karnofsky score (P<0.001). Multivariate analysis and the data from the current study demonstrated that sex, tumor stage and size, surgery, chemoradiotherapy, and the aforementioned eight SNPs were all independent predictors for overall survival of lung cancer patients.

  • Research article

    Cloning, purification and characterization of translationally fused protein DNA methyltransferase M•HhaI-EGFP

    Process Biochemistry, Volume 49, Issue 12, 2014, pp. 2170-2173

    Design of the transcriptionally-fused protein M•HhaI-EGFP, composed of bacterial DNA-methyltransferase M•HhaI and enhanced green fluorescent protein (GFP) is described. The mentioned M•HhaI-EGFP was expressed in Escherichia coli ER1821 and purified by affinity chromatography on Ni-NTA agarose. According to expectations M•HhaI-EGFP fused protein retained significant features of corresponding original proteins: the ability to transfer methyl group to the C5 carbon atom of internal cytosine in CGCG site and absorption–emission spectral characteristics. The created transcriptionally-fused protein M•HhaI-EGFP could be used in various experiments in molecular biology.

© 2023 Elsevier Ltd. All rights reserved.

(Video) Targeting cancer cell metabolism


1. 34. Reactive Oxygen Species 4 & Nucleotide Metabolism 1
(MIT OpenCourseWare)
2. Regulating metabolism to boost the immune response against cancer
3. Clinical Disorders of Purine and Pyrimidine Metabolism/ Biochemistry
(Medical Biochemistry For Medical Students)
4. Purine Metabolism
(Medicosis Perfectionalis)
5. Greg Delgoffe - Metabolic control of T cell differentiation during immune responses to cancer
(IUIS Immunology Without Borders)
6. 32. Nucleotide Metabolism
(MIT OpenCourseWare)
Top Articles
Latest Posts
Article information

Author: Annamae Dooley

Last Updated: 05/12/2023

Views: 6688

Rating: 4.4 / 5 (65 voted)

Reviews: 80% of readers found this page helpful

Author information

Name: Annamae Dooley

Birthday: 2001-07-26

Address: 9687 Tambra Meadow, Bradleyhaven, TN 53219

Phone: +9316045904039

Job: Future Coordinator

Hobby: Archery, Couponing, Poi, Kite flying, Knitting, Rappelling, Baseball

Introduction: My name is Annamae Dooley, I am a witty, quaint, lovely, clever, rich, sparkling, powerful person who loves writing and wants to share my knowledge and understanding with you.