SIRT5 Deacetylates Carbamoyl Phosphate Synthetase 1 and Regulates the Urea Cycle

Takashi Nakagawa, David J. Lomb, Marcia C. Haigis, Leonard Guarente*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

668 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)560-570
Number of pages11
JournalCell
Volume137
Issue number3
DOIs
StatePublished - 2009/05/01

Keywords

  • CELLBIO
  • HUMDISEASE

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology

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