Journal Article

Quantitative analysis of amino acid metabolism in liver cancer links glutamate excretion to nucleotide synthesis

Engqvist, Martin, Klingmüller, Ursula, Nielsen, Jens, Gerding, Albert, Haanstra, Jurgen R., Teusink, Bas, Nilsson, Avlant, Bakker, Barbara M.

2020

Overview

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.

• Publisher: National Academy of Sciences
• Subject: Addictions / Adenosine triphosphate / Amino acids / ATP / Biological Sciences / Biophysics and Computational Biology / Cytosol / Excretion / Flux-balance analysis / Fluxes / Genome-scale modeling / Genomes / Glutamine / Hepatocytes / Intermediates / Liver / Liver cancer / Metabolic engineering / Metabolism / Nucleotides / Quantitative analysis / Replenishment / Synthesis / Systems biology / Therapeutic targets / Tricarboxylic acid cycle