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Amino acids downregulate SIRT4 to detoxify ammonia through the urea cycle.
- Source :
-
Nature metabolism [Nat Metab] 2023 Apr; Vol. 5 (4), pp. 626-641. Date of Electronic Publication: 2023 Apr 20. - Publication Year :
- 2023
-
Abstract
- Ammonia production via glutamate dehydrogenase is inhibited by SIRT4, a sirtuin that displays both amidase and non-amidase activities. The processes underlying the regulation of ammonia removal by amino acids remain unclear. Here, we report that SIRT4 acts as a decarbamylase that responds to amino acid sufficiency and regulates ammonia removal. Amino acids promote lysine 307 carbamylation (OTC <superscript>CP-K307</superscript> ) of ornithine transcarbamylase (OTC), which activates OTC and the urea cycle. Proteomic and interactome screening identified OTC as a substrate of SIRT4. SIRT4 decarbamylates OTC <superscript>CP-K307</superscript> and inactivates OTC in an NAD <superscript>+</superscript> -dependent manner. SIRT4 expression was transcriptionally upregulated by the amino acid insufficiency-activated GCN2-eIF2α-ATF4 axis. SIRT4 knockout in cultured cells caused higher OTC <superscript>CP-K307</superscript> levels, activated OTC, elevated urea cycle intermediates and urea production via amino acid catabolism. Sirt4 ablation decreased male mouse blood ammonia levels and ameliorated CCl <subscript>4</subscript> -induced hepatic encephalopathy phenotypes. We reveal that SIRT4 safeguards cellular ammonia toxicity during amino acid catabolism.<br /> (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)
- Subjects :
- Animals
Male
Mice
Cells, Cultured
Proteomics
Urea metabolism
Amino Acids
Ammonia
Subjects
Details
- Language :
- English
- ISSN :
- 2522-5812
- Volume :
- 5
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Nature metabolism
- Publication Type :
- Academic Journal
- Accession number :
- 37081161
- Full Text :
- https://doi.org/10.1038/s42255-023-00784-0