SIRT5 Deacetylates Carbamoyl Phosphate Synthetase 1 and Regulates the Urea Cycle

By T. Nakagawa, David J. Lomb, M. Haigis, L. Guarente. Cell, 2009

779 citations recorded by the source corpus.

Summary Sirtuins are NAD-dependent protein deacetylases that connect metabolism and aging. In mammals, there are seven sirtuins (SIRT1-7), three of which are associated with mitochondria. Here we show that SIRT5 localizes in the mitochondrial matrix and interacts with carbamoyl phosphate synthetase 1 (CPS1), an enzyme, catalyzing the initial step of the urea cycle for ammonia detoxification and disposal. SIRT5 deacetylates CPS1 and up-regulates its activity. During fasting, NAD in liver mitochondria increases, thereby triggering SIRT5 deacetylation of CPS1 and adaptation to the increase in amino acid catabolism. Indeed, SIRT5 KO mice fail to up-regulate CPS1 activity and show elevated blood ammonia during fasting. Similar effects occur during long-term calorie restriction or a high protein diet. These findings demonstrate SIRT5 plays a pivotal role in ammonia detoxification and disposal by activating CPS1.

Subfields: Geriatrics and Gerontology, Physiology

View Paper: https://www.semanticscholar.org/paper/da282e42f9ca4c624dc5ac09bf0a67149e68d8f4

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Geriatrics and Gerontology

1. Johan Auwerx
2. C. Cantó
3. E. Verdin
4. R. Houtkooper
5. M. Haigis
6. Keir J. Menzies
7. L. Guarente
8. Liangyou Rui

In Physiology

1. Johan Auwerx
2. E. Verdin
3. C. Cantó
4. R. Houtkooper
5. Keir J. Menzies
6. M. Haigis
7. Liangyou Rui
8. L. Guarente

Citations in the corpus

• The secret life of NAD+: an old metabolite controlling new metabolic signaling pathways. (2010, background): “5–4 mmol/kg protein (95, 123); 250 M (95) Cytosol Unknown Nucleus 70 M–estimate (241)”
• The Role of Sirtuins in Antioxidant and Redox Signaling (2017, background): “SIRT5 is popularly known for the regulation of mitochondrial fatty acid oxidation, the urea cycle, and cellular respiration (106, 183).”
• SIRT3 Deficiency and Mitochondrial Protein Hyperacetylation Accelerate the Development of the Metabolic Syndrome (2011, neutral): “, 2010); carbamoyl phosphate synthetase 1 (Nakagawa et al., 2009) and ornithine transcarbamoylase (Hallows et al.”
• Lysine Glutarylation Is a Protein Post-Translational Modification Regulated by SIRT5 (2014, background): “Because CPS1 was the protein identified with the highest level of glutarylation, and SIRT5 has been previously described to regulate CPS1 (Nakagawa et al., 2009), we sought to determine if glutarylation had a functional effect on CPS1 enzymatic activity and was regulated by SIRT5.”
• SIRT5-Mediated Lysine Desuccinylation Impacts Diverse Metabolic Pathways (2013, background): “We found that some proteins were highly succinylated, including CPS1 with 47 sites and (A) Histogram showing the ratio distribution of quantifiable Lys succinylation sites between Sirt5 KO and WT MEFs (see also Figure S3).”
• Sirtuins as regulators of metabolism and healthspan (2012, background): “SIRT5 was initially reported to deacetylate the urea cycle enzyme carbamoyl phosphate synthetase 1 (CPS1”
• Sirtuin Regulation of Mitochondria - Energy Production, Apoptosis, and Signaling (2010, background): “SIRT5 binds and deacetylates CPS1, stimulating its enzymatic activity [48].”
• Energy Metabolism in the Liver (2014, positive): “SIRT5 deacetylates and activates CPS-1 (188).”
• SIRT1 and other sirtuins in Metabolism (2013, background): “Deletion of the mitochondrial SIRT5 prevents the up-regulation of the urea cycle, which is required to reduce blood ammonia when amino acids serve as energy sources [27].”
• NAD+ metabolism and the control of energy homeostasis - a balancing act between mitochondria and the nucleus (2015, background): “Most reports indicate that mitochondrial NAD+ content is R250 mM (Nakagawa et al., 2009; Yang et al., 2007a), while according to indirect estimations, nuclear NAD+ levels seem to be much lower, 70 mM (Fjeld et al., 2003).”
• The First Identification of Lysine Malonylation Substrates and Its Regulatory Enzyme* (2011, background): “Sirt5 was shown to deacetylate this protein and increase its activity (19).”
• Calorie restriction reduces oxidative stress by SIRT3-mediated SOD2 activation. (2010, background): “CR induces an increase in the expression of SIRT3 (Palacios et al., 2009; Shi et al., 2005) and mitochondrial NAD+ levels (Nakagawa et al., 2009), suggesting that SIRT3 activity is likely to be upregulated during CR.”