SIRT5 deacetylates carbamoyl phosphate synthetase 1 and regulates the urea cycle
Open accessAbstract
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 upregulates 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 upregulate 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.
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CPS1 is a target of lysine acetylation, succinylation, glutarylation, and malonylation.
“CPS1, which catalyzes the initial step of the urea cycle by synthesizing carbamoyl phosphate from ammonia and bicarbonate, is a target of lysine acetylation, succinylation, glutarylation and malonylation ((Nakagawa et al. 2009))((Rardin, Newman, et al. 2013))((Du et al. 2011))((Rardin, He, et al. 2013))((Park et al. 2013))((Tan et al. 2014))((Nishida et al. 2015)).”
From The Mitochondrial Acylome Emerges: Proteomics, Regulation by Sirtuins, and Metabolic and Disease Implications (2018) · cites this paper as Nakagawa et al. 2009
SIRT5 positively regulates CPS1 activity by mediating desuccinylation, deglutarylation, and possibly deacetylation across multiple sites.
“SIRT5 positively regulates CPS1 activity by mediating desuccinylation, deglutarylation and possibly by deacetylation across multiple sites ((Du et al. 2011))((Tan et al. 2014))((Nakagawa et al. 2009)).”
From The Mitochondrial Acylome Emerges: Proteomics, Regulation by Sirtuins, and Metabolic and Disease Implications (2018) · cites this paper as Nakagawa et al. 2009
Mice lacking SIRT5 fail to upregulate CPS1 activity and show elevated blood ammonia under fasting, calorie restriction, or high protein diet.
“Mice lacking SIRT5 fail to upregulate CPS1 activity and show elevated blood ammonia under these conditions ((Nakagawa et al. 2009))((Tan et al. 2014)).”
From The Mitochondrial Acylome Emerges: Proteomics, Regulation by Sirtuins, and Metabolic and Disease Implications (2018) · cites this paper as Nakagawa et al. 2009
CPS1 has at least 52 acetylated, 44 succinylated, 33 glutarylated, and 29 malonylated lysine sites.
“At least 52 lysine sites are found to be acetylated, 44 sites succinylated, 33 sites glutarylated and 29 sites malonylated.”
From The Mitochondrial Acylome Emerges: Proteomics, Regulation by Sirtuins, and Metabolic and Disease Implications (2018) · cites this paper as Nakagawa et al. 2009
The urea cycle was the first metabolic pathway found to be regulated by mitochondrial sirtuins.
“The urea cycle was the first metabolic pathway found to be regulated by mitochondrial sirtuins ((Nakagawa et al. 2009)).”
From The Mitochondrial Acylome Emerges: Proteomics, Regulation by Sirtuins, and Metabolic and Disease Implications (2018) · cites this paper as Nakagawa et al. 2009
SIRT5 promotes urea cycle function via regulation of CPS1.
“SIRT5 promotes urea cycle function via the regulation of carbamoyl phosphate synthase (CPS1) (Nakagawa et al., 2009; Ogura et al., 2010)”
From SIRT5-mediated lysine desuccinylation impacts diverse metabolic pathways (2013) · cites this paper as Nakagawa et al., 2009
SIRT5 is thought to localize primarily to mitochondria.
“SIRT5 is thought to localize primarily to mitochondria (Lombard et al., 2007; Michishita et al., 2005; Nakagawa et al., 2009; Schlicker et al., 2008).”
From SIRT5-mediated lysine desuccinylation impacts diverse metabolic pathways (2013) · cites this paper as Nakagawa et al., 2009
The SIRT5H158Y mutant has reduced desuccinylase activity.
“a SIRT5H158Y mutant showed hypomorphic desuccinylase activity (Nakagawa et al., 2009).”
From SIRT5-mediated lysine desuccinylation impacts diverse metabolic pathways (2013) · cites this paper as Nakagawa et al., 2009
SIRT5 removes posttranslational modifications including malonylation, glutarylation, and succinylation on lysine residues.
“SIRT5, a member of the nicotinamide adenine dinucleotide-dependent sirtuin family of protein deacetylases, removes posttranslational modifications including malonylation, glutarylation, and succinylation on lysine residues [204,205].”
From AMPK, Mitochondrial Function, and Cardiovascular Disease (2020) · cites this paper as [205]
CPS is deacetylated by SIRT5 during fasting.
“For example, the urea cycle enzyme carbamoyl phosphate synthetase (CPS) is deacetylated by the sirtuin SIRT5 during fasting (Nakagawa et al., 2009).”
From Cellular Metabolism and Disease: What Do Metabolic Outliers Teach Us? (2012) · cites this paper as Nakagawa et al., 2009
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- Authors
- Nakagawa, T., Lomb, D. J., Haigis, M. C., & Guarente, L.
- Affiliations
- Massachusetts Institute of Technology (US)
- Harvard University (US)
- Corresponding author
- Guarente, Leonard
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2009-05
- Volume
- 137
- Issue
- 3
- Pages
- 560-570
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC2698666
- OpenAlex
- W2059750004
- Cited by
- 787
- References
- 57
- Citations by year
- 2026: 26 · 2025: 39 · 2024: 35 · 2023: 32 · 2022: 49 · 2021: 54 · 2020: 40 · 2019: 43 · 2018: 53 · 2017: 41 · 2016: 53 · 2015: 51 · 2014: 43 · 2013: 61 · 2012: 59
- FWCI
- 39.82
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 1574 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- Funders
- National Institute on Aging (R01AG015339, R01AG011119)
- Topics
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Keywords
- SIRT5, CPS1, urea cycle, protein deacetylation, ammonia detoxification, fasting, caloric restriction, high-protein diet, mitochondrial matrix, sirtuins, NAD+ metabolism, amino acid catabolism, blood ammonia
- MeSH terms
- Ammonia, Animals, Carbamoyl-Phosphate Synthase (Ammonia), Cells, Cultured, Enzyme Activation, Humans, Mitochondria, Liver, Substrate Specificity, Mitochondrial Proteins, Sirtuins, Mice
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