Hepatic glutamine synthetase controls N5-methylglutamine in homeostasis and cancer

Villar, V. H. et al. (2023) Hepatic glutamine synthetase controls N5-methylglutamine in homeostasis and cancer. Nature Chemical Biology, 19(3), pp. 292-300. (doi: 10.1038/s41589-022-01154-9) (PMID:36280791) (PMCID:PMC9974483)

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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.

Item Type:Articles
Additional Information:This work was funded by Cancer Research UK awards A17196 and A31287 (CRUK Beatson Institute), Cancer Research UK RadNet Glasgow Centre award A28803 (A.B.), Wellcome Trust grant WT107492Z (T.G.B. and M.M.), Cancer Research UK HUNTER accelerator award A26813 (E.H.T.), Cancer Research UK award A25045 and DRCQQR-May21\100002 (O.J.S.), Cancer Research UK award A29256 (D.T.H.), Cancer Research UK award A29799 (K.B.), Cancer Research UK award A25006 (D.Y.L.) and Cancer Research UK award A23982 (S.T.).
Glasgow Author(s) Enlighten ID:Lewis, Dr David and Tan, Dr Ee and May, Dr Steph and Nixon, Mr Colin and Allega, Maria Francesca and Tardito, Dr Saverio and Blyth, Professor Karen and Drake, Dr Tom and Murphy, Professor Daniel and Sumpton, Mr David and Huang, Professor Danny and Nakasone, Dr Mark and Bird, Dr Thomas and Sansom, Professor Owen
Authors: Villar, V. H., Allega, M. F., Deshmukh, R., Ackermann, T., Nakasone, M. A., Vande Voorde, J., Drake, T. M., Oetjen, J., Bloom, A., Nixon, C., Müller, M., May, S., Tan, E. H., Vereecke, L., Jans, M., Blancke, G., Murphy, D. J., Huang, D. T., Lewis, D. Y., Bird, T. G., Sansom, O. J., Blyth, K., Sumpton, D., and Tardito, S.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:Nature Chemical Biology
Publisher:Nature Research
ISSN (Online):1552-4469
Published Online:24 October 2022
Copyright Holders:Copyright © 2022 The Authors
First Published:First published in Nature Chemical Biology 19(3): 292-300
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
306407Glasgow RadNet CentreAnthony ChalmersCancer Research UK (CRUK)C16583/A28803CS - Clinical Trials Research
301496HUNTER: Hepatocellular Carcinoma Expediter NetworkThomas BirdCancer Research UK (CRUK)BH172934 - C9380/A26813CS - Experimental Therapeutics