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)
Text
284447.pdf - Published Version Available under License Creative Commons Attribution. 6MB |
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.
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.). |
Status: | Published |
Refereed: | Yes |
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: | 1552-4450 |
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 |
University Staff: Request a correction | Enlighten Editors: Update this record