Stimulation of de novo pyrimidine synthesis by growth signaling through mTOR and S6K1
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Coordinating Metabolism: Growth factors help to coordinate metabolism with growth in part by stimulating the activity of the protein kinase mTORC1 (mechanistic target of rapamycin complex 1). Ben-Sahra et al. (p. 1323 , published online 21 February) and Robitaille et al. (p. 1320 , published online 21 February) independently identified a key target of mTORC1—carbamolyl-phosphate synthase 2, or CAD, the rate-limiting enzyme for de novo synthesis of pyrimidines. Metabolomic profiling and phosphoproteomic analyses of normal cells and cells lacking signaling by mTORC1 converged on CAD as a key point at which growth-promoting signals also ramp up production of nucleic acids.
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Activation of mTOR can increase ribose synthesis via the oxidative pentose phosphate pathway and enhance flux through pyrimidine and purine synthesis pathways.
“Activation of mTOR can increase ribose synthesis via the oxidative pentose phosphate pathway (Duvel et al., 2010) and enhance flux through the pyrimidine and purine synthesis pathways (Ben-Sahra et al., 2013; Ben-Sahra et al., 2016; Robitaille et al., 2013), suggesting that targeting nucleotide metabolism in tumor contexts with mTOR hyperactivation may be more effective.”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Ben-Sahra et al., 2013
Targeting nucleotide metabolism may be more effective in tumor contexts with mTOR hyperactivation.
“Activation of mTOR can increase ribose synthesis via the oxidative pentose phosphate pathway (Duvel et al., 2010) and enhance flux through the pyrimidine and purine synthesis pathways (Ben-Sahra et al., 2013; Ben-Sahra et al., 2016; Robitaille et al., 2013), suggesting that targeting nucleotide metabolism in tumor contexts with mTOR hyperactivation may be more effective.”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Ben-Sahra et al., 2013
Glutamine-induced activation of mTORC1 results in phosphorylation of CAD, which catalyzes the condensation reaction converting glutamine-derived nitrogen into the pyrimidine precursor orotate.
“Moreover, glutamine-induced activation of mTORC1 results in the phosphorylation of the enzyme complex called carbamoyl phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD), which catalyzes the condensation reaction converting glutamine-derived nitrogen into the pyrimidine precursor orotate34,35.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [34]
CAD activity is regulated via phosphorylation by MAPK and by mTORC1-dependent S6 kinase.
“Furthermore, activity of CAD enzyme is regulated via phosphorylation by MAPK and by mTORC1-dependent S6 kinase (Ben-Sahra et al., 2013; Graves et al., 2000; Robitaille et al., 2013).”
From The emerging hallmarks of cancer metabolism (2016) · cites this paper as Ben-Sahra et al., 2013
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- Authors
- Ben-Sahra, I., Howell, J. J., Asara, J. M., & Manning, B. D.
- Affiliations
- Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA 02115, USA.
- Harvard University (US)
- Beth Israel Deaconess Medical Center (US)
- Corresponding author
- Howell, Jessica J.
- Manning, Brendan D.
- Venue
- Science
- Published
- 2013-03-15
- Volume
- 339
- Issue
- 6125
- Pages
- 1323-1328
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC3753690
- OpenAlex
- W1982789056
- Cited by
- 739
- References
- 23
- Citations by year
- 2026: 35 · 2025: 48 · 2024: 41 · 2023: 43 · 2022: 75 · 2021: 74 · 2020: 64 · 2019: 61 · 2018: 57 · 2017: 63 · 2016: 51 · 2015: 55 · 2014: 49 · 2013: 23
- FWCI
- 26.56
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (R01CA122617, P01CA120964, P30CA006516)
- National Institute of Diabetes and Digestive and Kidney Diseases (F32DK095508)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- de novo pyrimidine biosynthesis, mTORC1, S6K1, growth signaling, anabolic metabolism, S6K, ribosome biogenesis, nucleotide synthesis, protein kinase signaling
- MeSH terms
- Mechanistic Target of Rapamycin Complex 1, Tuberous Sclerosis Complex 2 Protein, Animals, Aspartate Carbamoyltransferase, Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing), Dihydroorotase, HeLa Cells, Humans, Pyrimidines, Signal Transduction, Ribosomal Protein S6 Kinases, Tumor Suppressor Proteins, 3T3-L1 Cells, Multiprotein Complexes, Mice, TOR Serine-Threonine Kinases
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