Abstract
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. Exogenous asparagine can rescue growth and survival of glutamine-deprived cells. Pavlova et al. show that asparagine is not catabolized to produce other amino acids or biosynthetic intermediates, but rather maintains protein synthesis. Introduction of asparaginase suppressed the growth and survival of glutamine-depleted cells and compromised the growth of tumor xenografts.
| Original language | English (US) |
|---|---|
| Journal | Cell Metabolism |
| DOIs | |
| State | Accepted/In press - Jan 1 2018 |
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Keywords
- Asparaginase
- Asparagine
- Glutamine
- Translation
ASJC Scopus subject areas
- Physiology
- Molecular Biology
- Cell Biology
Cite this
As Extracellular Glutamine Levels Decline, Asparagine Becomes an Essential Amino Acid. / Pavlova, Natalya N.; Hui, Sheng; Ghergurovich, Jonathan M.; Fan, Jing; Intlekofer, Andrew M.; White, Richard M.; Rabinowitz, Joshua D.; Thompson, Craig B.; Zhang, Ji.
In: Cell Metabolism, 01.01.2018.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - As Extracellular Glutamine Levels Decline, Asparagine Becomes an Essential Amino Acid
AU - Pavlova, Natalya N.
AU - Hui, Sheng
AU - Ghergurovich, Jonathan M.
AU - Fan, Jing
AU - Intlekofer, Andrew M.
AU - White, Richard M.
AU - Rabinowitz, Joshua D.
AU - Thompson, Craig B.
AU - Zhang, Ji
PY - 2018/1/1
Y1 - 2018/1/1
N2 - 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. Exogenous asparagine can rescue growth and survival of glutamine-deprived cells. Pavlova et al. show that asparagine is not catabolized to produce other amino acids or biosynthetic intermediates, but rather maintains protein synthesis. Introduction of asparaginase suppressed the growth and survival of glutamine-depleted cells and compromised the growth of tumor xenografts.
AB - 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. Exogenous asparagine can rescue growth and survival of glutamine-deprived cells. Pavlova et al. show that asparagine is not catabolized to produce other amino acids or biosynthetic intermediates, but rather maintains protein synthesis. Introduction of asparaginase suppressed the growth and survival of glutamine-depleted cells and compromised the growth of tumor xenografts.
KW - Asparaginase
KW - Asparagine
KW - Glutamine
KW - Translation
UR - http://www.scopus.com/inward/record.url?scp=85040368570&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85040368570&partnerID=8YFLogxK
U2 - 10.1016/j.cmet.2017.12.006
DO - 10.1016/j.cmet.2017.12.006
M3 - Article
C2 - 29337136
AN - SCOPUS:85040368570
JO - Cell Metabolism
JF - Cell Metabolism
SN - 1550-4131
ER -