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Urea cycle regulation by mitochondrial sirtuin, SIRT5.

Nakagawa T, Guarente L - Aging (Albany NY) (2009)

Bottom Line: Recently we reported a new function for SIRT5 in urea cycle regulation.Our study uncovered that SIRT5 localized to mitochondria matrix and deacetylates carbamoyl phosphate synthetase 1 (CPS1), an enzyme which is the first and rate-limiting step of urea cycle.Deacetylation of CPS1 by SIRT5 resulted in activation of CPS1 enzymatic activity.

View Article: PubMed Central - PubMed

Affiliation: Paul F. Glenn Laboratory for the Science of Aging and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

ABSTRACT
Mammalian sirtuins have diverse roles in aging, metabolism and disease. Recently we reported a new function for SIRT5 in urea cycle regulation. Our study uncovered that SIRT5 localized to mitochondria matrix and deacetylates carbamoyl phosphate synthetase 1 (CPS1), an enzyme which is the first and rate-limiting step of urea cycle. Deacetylation of CPS1 by SIRT5 resulted in activation of CPS1 enzymatic activity. Indeed, SIRT5-deficient mice failed to up-regulate CPS1 activity and showed hyper ammonemia during fasting. Similar effects are also observed on high protein diet or calorie restriction. These data indicate SIRT5 also has an emerging role in the metabolic adaptation to fasting, high protein diet and calorie restriction.

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How SIRT5 is regulated during fasting and CR.
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Figure 1: How SIRT5 is regulated during fasting and CR.

Mentions: Recently we reported that SIRT5 is localized in mitochondria matrix and regulates the urea cycle through the deacetylation of CPS1 (Figure 1) [9]. By systemic sub-fractionation of isolated mitochondria from mouse liver, we found SIRT5 was also localized in the matrix fraction, as well as SIRT3 and SIRT4. This finding corresponded with the fact that SIRT5 was cleaved in the N-terminus at a typical consensus sequence recognized by mitochondria matrix peptidase. To identify SIRT5-interacting proteins, we developed In vitro SIRT5-Flag affinity purification, and found CPS1 as a SIRT5-binding protein. CPS1 is an enzyme which mediates the first step of urea cycle. CPS1 is reported to be acetylated at multiple lysine residues [10], however the biological function of acetylation was unclear. Using an in vitro deacetylation assay, we revealed that SIRT5 could deacetylate CPS1 in a NAD-dependent manner and this deacetylation increased CPS1 enzymatic activity. Indeed, SIRT5 deficient mice have ~30% lower CPS1 activity compared to wild type mice. During fasting conditions, SIRT5 deficient mice failed to up-regulate CPS1 activity and thereby resulted in hyper ammonemia. Similar results were observed during calorie restriction or a high protein diet.


Urea cycle regulation by mitochondrial sirtuin, SIRT5.

Nakagawa T, Guarente L - Aging (Albany NY) (2009)

How SIRT5 is regulated during fasting and CR.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2806029&req=5

Figure 1: How SIRT5 is regulated during fasting and CR.
Mentions: Recently we reported that SIRT5 is localized in mitochondria matrix and regulates the urea cycle through the deacetylation of CPS1 (Figure 1) [9]. By systemic sub-fractionation of isolated mitochondria from mouse liver, we found SIRT5 was also localized in the matrix fraction, as well as SIRT3 and SIRT4. This finding corresponded with the fact that SIRT5 was cleaved in the N-terminus at a typical consensus sequence recognized by mitochondria matrix peptidase. To identify SIRT5-interacting proteins, we developed In vitro SIRT5-Flag affinity purification, and found CPS1 as a SIRT5-binding protein. CPS1 is an enzyme which mediates the first step of urea cycle. CPS1 is reported to be acetylated at multiple lysine residues [10], however the biological function of acetylation was unclear. Using an in vitro deacetylation assay, we revealed that SIRT5 could deacetylate CPS1 in a NAD-dependent manner and this deacetylation increased CPS1 enzymatic activity. Indeed, SIRT5 deficient mice have ~30% lower CPS1 activity compared to wild type mice. During fasting conditions, SIRT5 deficient mice failed to up-regulate CPS1 activity and thereby resulted in hyper ammonemia. Similar results were observed during calorie restriction or a high protein diet.

Bottom Line: Recently we reported a new function for SIRT5 in urea cycle regulation.Our study uncovered that SIRT5 localized to mitochondria matrix and deacetylates carbamoyl phosphate synthetase 1 (CPS1), an enzyme which is the first and rate-limiting step of urea cycle.Deacetylation of CPS1 by SIRT5 resulted in activation of CPS1 enzymatic activity.

View Article: PubMed Central - PubMed

Affiliation: Paul F. Glenn Laboratory for the Science of Aging and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

ABSTRACT
Mammalian sirtuins have diverse roles in aging, metabolism and disease. Recently we reported a new function for SIRT5 in urea cycle regulation. Our study uncovered that SIRT5 localized to mitochondria matrix and deacetylates carbamoyl phosphate synthetase 1 (CPS1), an enzyme which is the first and rate-limiting step of urea cycle. Deacetylation of CPS1 by SIRT5 resulted in activation of CPS1 enzymatic activity. Indeed, SIRT5-deficient mice failed to up-regulate CPS1 activity and showed hyper ammonemia during fasting. Similar effects are also observed on high protein diet or calorie restriction. These data indicate SIRT5 also has an emerging role in the metabolic adaptation to fasting, high protein diet and calorie restriction.

Show MeSH
Related in: MedlinePlus