TitleAs Extracellular Glutamine Levels Decline, Asparagine Becomes an Essential Amino Acid.
Publication TypeJournal Article
Year of Publication2018
AuthorsPavlova, NN, Hui, S, Ghergurovich, JM, Fan, J, Intlekofer, AM, White, RM, Rabinowitz, JD, Thompson, CB, Zhang, J
JournalCell Metab
Date Published2018 02 06
KeywordsAmino Acids, Essential, Animals, Asparaginase, Asparagine, Cell Line, Cell Line, Tumor, Cell Proliferation, Extracellular Space, Female, Glutamine, Humans, Mammals, Mice, Inbred C57BL, Protein Biosynthesis, Substrate Specificity

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.

Alternate JournalCell Metab.
PubMed ID29337136
PubMed Central IDPMC5803449
Grant ListP30 CA008748 / CA / NCI NIH HHS / United States