SIRT5 Deacetylates Carbamoyl Phosphate Synthetase 1 and Regulates the Urea Cycle
Author(s)Nakagawa, Takashi; Lomb, David J.; Haigis, Marcia C.; Guarente, Leonard Pershing
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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.
DepartmentMassachusetts Institute of Technology. Department of Biology; Massachusetts Institute of Technology. Glenn Laboratory for the Science of Aging
Nakagawa, Takashi, David J. Lomb, Marcia C. Haigis, and Leonard Guarente. “SIRT5 Deacetylates Carbamoyl Phosphate Synthetase 1 and Regulates the Urea Cycle.” Cell 137, no. 3 (May 2009): Copyright © 2009 Elsevier Inc.
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