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. 2009 Jun 29;1(6):578-81.
doi: 10.18632/aging.100062.

Urea cycle regulation by mitochondrial sirtuin, SIRT5

Takashi Nakagawa  1 , Leonard Guarente
Affiliations

Urea cycle regulation by mitochondrial sirtuin, SIRT5

Takashi Nakagawa et al. Aging (Albany NY). .

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.

Keywords: CPS1; SIRT5; deacetylation; mitochondria; sirtuin; urea cycle.

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Conflict of interest statement

L.G. is a consultant for Sirtris Pharmaceuticals.

Figures

Figure 1.
Figure 1.. How SIRT5 is regulated during fasting and CR.
Figure 2.
Figure 2.. Ammonia detoxification pathway and mitochondrial sirtuins.
See this image and copyright information in PMC

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