학술논문
Hepatic glutamine synthetase controls N5-methylglutamine in homeostasis and cancer
Document Type
Article
Author
Villar, Victor H.; Allega, Maria Francesca; Deshmukh, Ruhi; Ackermann, Tobias; Nakasone, Mark A.; Vande Voorde, Johan; Drake, Thomas M.; Oetjen, Janina; Bloom, Algernon; Nixon, Colin; Müller, Miryam; May, Stephanie; Tan, Ee Hong; Vereecke, Lars; Jans, Maude; Blancke, Gillian; Murphy, Daniel J.; Huang, Danny T.; Lewis, David Y.; Bird, Thomas G.; Sansom, Owen J.; Blyth, Karen; Sumpton, David; Tardito, Saverio
Source
Nature Chemical Biology; 20220101, Issue: Preprints p1-9, 9p
Subject
Language
ISSN
15524450; 15524469
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.