As Extracellular Glutamine Levels Decline, Asparagine Becomes an Essential Amino Acid
Open accessAbstract
When mammalian cells are deprived of glutamine, exogenous asparagine rescues cell survival and growth. Here we report that this rescue results from use of asparagine in protein synthesis. All mammalian cell lines tested lacked cytosolic asparaginase activity and could not utilize asparagine to produce other amino acids or biosynthetic intermediates. Instead, most glutamine-deprived cell lines are capable of sufficient glutamine synthesis to maintain essential amino acid uptake and production of glutamine-dependent biosynthetic precursors, with the exception of asparagine. While experimental introduction of cytosolic asparaginase could enhance the synthesis of glutamine and increase tricarboxylic acid cycle anaplerosis and the synthesis of nucleotide precursors, cytosolic asparaginase suppressed the growth and survival of cells in glutamine-depleted medium in vitro and severely compromised the in vivo growth of tumor xenografts. These results suggest that the lack of asparaginase activity represents an evolutionary adaptation to allow mammalian cells to survive pathophysiologic variations in extracellular glutamine.
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Glutamate supplementation during glutamine deprivation cannot rescue impaired cell growth or mitochondrial respiration, indicating that mitochondrial GLS-catalyzed cleavage of the gamma-nitrogen of glutamine is essential for glutaminolysis.
“Although glutamate is the major downstream product of glutamine, glutamate supplementation during glutamine deprivation cannot rescue the impaired cell growth or mitochondrial respiration16,43–45, indicating that mitochondrial GLS-catalyzed cleavage of the gamma-nitrogen of glutamine is essential for glutaminolysis.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [45]
Asparagine supplementation enhances expression of GLUL and increases intracellular glutamine usage via glutaminolysis, resulting in recovery of global protein translation blocked by glutamine deprivation.
“Instead, asparagine supplementation enhances the expression of glutamine synthetase (GLUL) and increases intracellular glutamine usage via glutaminolysis, resulting in the recovery of global protein translation that is blocked by glutamine deprivation45.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [45]
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- Authors
- Pavlova, N. N., Hui, S., Ghergurovich, J. M., Fan, J., Intlekofer, A. M., White, R. M., Rabinowitz, J. D., Thompson, C. B., & Zhang, J.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Princeton University (US)
- Corresponding author
- Thompson, Craig B.
- Zhang, Ji
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2018-02
- Volume
- 27
- Issue
- 2
- Pages
- 428-438.e5
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC5803449
- OpenAlex
- W2783201301
- Cited by
- 341
- References
- 42
- Citations by year
- 2026: 39 · 2025: 40 · 2024: 50 · 2023: 42 · 2022: 46 · 2021: 38 · 2020: 39 · 2019: 29 · 2018: 17
- FWCI
- 13.29
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- IUScholarWorks (Indiana University) (submittedVersion)
- Purdue University Indianapolis (Indiana University) (submittedVersion)
- PMC
- Funders
- National Cancer Institute (P30 CA008748)
- Terri Brodeur Breast Cancer Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
- Keywords
- asparagine, glutamine deprivation, essential amino acids, protein synthesis, glutamine synthesis, nucleotide synthesis, tumor xenografts, amino acid metabolism, cell survival
- MeSH terms
- Amino Acids, Essential, Animals, Asparaginase, Asparagine, Cell Line, Extracellular Space, Female, Glutamine, Humans, Mammals, Mice, Inbred C57BL, Substrate Specificity, Protein Biosynthesis, Cell Line, Tumor, Cell Proliferation
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