Quantitative analysis of amino acid metabolism in liver cancer links glutamate excretion to nucleotide synthesis
Artikel i vetenskaplig tidskrift, 2020

Many cancer cells consume glutamine at high rates; counterintuitively, they simultaneously excrete glutamate, the first intermediate in glutamine metabolism. Glutamine consumption has been linked to replenishment of tricarboxylic acid cycle (TCA) intermediates and synthesis of adenosine triphosphate (ATP), but the reason for glutamate excretion is unclear. Here, we dynamically profile the uptake and excretion fluxes of a liver cancer cell line (HepG2) and use genome-scale metabolic modeling for in-depth analysis. We find that up to 30% of the glutamine is metabolized in the cytosol, primarily for nucleotide synthesis, producing cytosolic glutamate. We hypothesize that excreting glutamate helps the cell to increase the nucleotide synthesis rate to sustain growth. Indeed, we show experimentally that partial inhibition of glutamate excretion reduces cell growth. Our integrative approach thus links glutamine addiction to glutamate excretion in cancer and points toward potential drug targets.

Flux-balance analysis

Systems biology

Genome-scale modeling

Metabolic engineering


Avlant Nilsson

Chalmers, Biologi och bioteknik, Systembiologi

J. R. Haanstra

Vrije Universiteit Amsterdam

Martin Engqvist

Chalmers, Biologi och bioteknik, Systembiologi

Albert Gerding

Rijksuniversiteit Groningen

Barbara M. Bakker

Vrije Universiteit Amsterdam

Rijksuniversiteit Groningen

Ursula Klingmüller

Deutsches Krebsforschungszentrum (DKFZ)

B. Teusink

Vrije Universiteit Amsterdam

Jens B Nielsen

Danmarks Tekniske Universitet (DTU)

Chalmers, Biologi och bioteknik, Systembiologi

Proceedings of the National Academy of Sciences of the United States of America

0027-8424 (ISSN) 1091-6490 (eISSN)

Vol. 117 19 10294-10304



Annan medicinsk bioteknologi

Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci)



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