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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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Ammonia detoxification pathway and mitochondrial sirtuins.
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Figure 2: Ammonia detoxification pathway and mitochondrial sirtuins.

Mentions: Interestingly, SIRT4 ADP-ribosylates GDH, which mediates the oxidative deamination step during ammonia detoxification and represses GDH activity (Figure 2). Our findings show that SIRT5 controls the subsequent step of the ammonia detoxification pathway. Furthermore, OTC, an enzyme mediating the second step of the urea cycle in the mitochondria matrix, was also recently reported to be regulated by reversible acetylation of Lysine-88 [12]. Deacetylation of OTC Lysine-88 increases the OTC enzymatic activity. In our study, no obvious change was observed in OTC activity in SIRT3, SIRT4 and SIRT5 deficient mice under normal conditions. However, a more detailed study under stressed condition, such as fasting or calorie restriction may reveal the roles of mitochondrial sirtuins in OTC deacetylation and the coordination of mitochondrial sirtuins in the ammonia detoxification pathway.


Urea cycle regulation by mitochondrial sirtuin, SIRT5.

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

Ammonia detoxification pathway and mitochondrial sirtuins.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: Ammonia detoxification pathway and mitochondrial sirtuins.
Mentions: Interestingly, SIRT4 ADP-ribosylates GDH, which mediates the oxidative deamination step during ammonia detoxification and represses GDH activity (Figure 2). Our findings show that SIRT5 controls the subsequent step of the ammonia detoxification pathway. Furthermore, OTC, an enzyme mediating the second step of the urea cycle in the mitochondria matrix, was also recently reported to be regulated by reversible acetylation of Lysine-88 [12]. Deacetylation of OTC Lysine-88 increases the OTC enzymatic activity. In our study, no obvious change was observed in OTC activity in SIRT3, SIRT4 and SIRT5 deficient mice under normal conditions. However, a more detailed study under stressed condition, such as fasting or calorie restriction may reveal the roles of mitochondrial sirtuins in OTC deacetylation and the coordination of mitochondrial sirtuins in the ammonia detoxification pathway.

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