Hepatic glutamine synthetase controls N5-methylglutamine in homeostasis and cancer

Victor H Villar, Maria Francesca Allega, Ruhi Deshmukh, Tobias Ackermann, Mark A. Nakasone, Johan Vande Voorde, Thomas Drake, Janina Oetjen, Algernon Bloom, Colin Nixon, Lars Vereecke, Maude Jans, Gillian Blancke, Thomas G Bird, David Lewis, Owen J Sansom, Karen Blyth, David Sumpton, Saverio Tardito*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

Glutamine synthetase (GS) is the only known enzyme that synthesizes glutamine in mammals. Here we show that mammalian GS utilizes glutamate and methylamine to produce a methylated glutamine analogue, N5-methylglutamine. Untargeted metabolomics revealed that liver-specific deletion of Glul and pharmacologic inhibition of GS, suppress the hepatic and circulating levels of N5-methylglutamine in mice. Conversely, N5-methylglutamine levels are sustained by the metabolism of gut microbiome. This alternative activity of GS was confirmed using human recombinant enzyme and cells where a pathogenic mutation promotes the synthesis of N5-methylglutamine over glutamine. Finally, we show that the urine level of N5-methylglutamine correlates with tumour burden in a novel -catenin-driven model of liver cancer with high GS expression, disclosing the potential of N5-methylglutamine as a biomarker for GS-positive hepatocellular carcinoma.
Original languageEnglish
JournalNature Chemical Biology
Early online date24 Oct 2022
Publication statusE-pub ahead of print - 24 Oct 2022


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