Hepatic glutamine synthetase controls N5-methylglutamine in homeostasis and cancer.
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| Abstract |
Glutamine synthetase (GS) activity is conserved from prokaryotes to humans, where the ATP-dependent production of glutamine from glutamate and ammonia is essential for neurotransmission and ammonia detoxification. Here, we show that mammalian GS uses glutamate and methylamine to produce a methylated glutamine analog, N5-methylglutamine. Untargeted metabolomics revealed that liver-specific GS deletion and its pharmacological inhibition in mice suppress hepatic and circulating levels of N5-methylglutamine. This alternative activity of GS was confirmed in human recombinant enzyme and cells, where a pathogenic mutation in the active site (R324C) promoted the synthesis of N5-methylglutamine over glutamine. N5-methylglutamine is detected in the circulation, and its levels are sustained by the microbiome, as demonstrated by using germ-free mice. Finally, we show that urine levels of N5-methylglutamine correlate with tumor burden and GS expression in a β-catenin-driven model of liver cancer, highlighting the translational potential of this uncharacterized metabolite.
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| Authors | Victor H Villar, Maria Francesca Allega, Ruhi Deshmukh, Tobias Ackermann, Mark A Nakasone, Johan Vande Voorde, Thomas M Drake, Janina Oetjen, Algernon Bloom, Colin Nixon, Miryam Müller, Stephanie May, Ee Hong Tan, Lars Vereecke, Maude Jans, Gillian Blancke, Daniel J Murphy, Danny T Huang, David Y Lewis, Thomas G Bird, Owen J Sansom, Karen Blyth, David Sumpton, Saverio Tardito |
| Journal | Nature chemical biology (Nat Chem Biol) Vol. 19 Issue 3 Pg. 292-300 (03 2023) ISSN: 1552-4469 [Electronic] United States |
| PMID | 36280791 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
| Copyright | © 2022. The Author(s). |
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