As Extracellular Glutamine Levels Decline, Asparagine Becomes an Essential Amino Acid

Natalya N. Pavlova, Sheng Hui, Jonathan M. Ghergurovich, Jing Fan, Andrew M. Intlekofer, Richard M. White, Joshua D. Rabinowitz, Craig B. Thompson, Ji Zhang

Research output: Contribution to journalArticle

30 Citations (Scopus)

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 languageEnglish (US)
JournalCell Metabolism
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Essential Amino Acids
Asparagine
Glutamine
Asparaginase
Growth
Heterografts
Cell Survival
Amino Acids
Cell Line
Citric Acid Cycle
Neoplasms
Proteins
Nucleotides

Keywords

  • Asparaginase
  • Asparagine
  • Glutamine
  • Translation

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

Cite this

Pavlova, N. N., Hui, S., Ghergurovich, J. M., Fan, J., Intlekofer, A. M., White, R. M., ... Zhang, J. (Accepted/In press). As Extracellular Glutamine Levels Decline, Asparagine Becomes an Essential Amino Acid. Cell Metabolism. https://doi.org/10.1016/j.cmet.2017.12.006

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 journalArticle

Pavlova, NN, Hui, S, Ghergurovich, JM, Fan, J, Intlekofer, AM, White, RM, Rabinowitz, JD, Thompson, CB & Zhang, J 2018, 'As Extracellular Glutamine Levels Decline, Asparagine Becomes an Essential Amino Acid', Cell Metabolism. https://doi.org/10.1016/j.cmet.2017.12.006
Pavlova, Natalya N. ; Hui, Sheng ; Ghergurovich, Jonathan M. ; Fan, Jing ; Intlekofer, Andrew M. ; White, Richard M. ; Rabinowitz, Joshua D. ; Thompson, Craig B. ; Zhang, Ji. / As Extracellular Glutamine Levels Decline, Asparagine Becomes an Essential Amino Acid. In: Cell Metabolism. 2018.
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