Hepatic glutamine synthetase controls N⁵-methylglutamine in homeostasis and cancer.

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 circula

SUBMITTER: Villar VH 

PROVIDER: S-EPMC9974483 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature