Overexpression of SIRT5 confirms its involvement in deacetylation and activation of carbamoyl phosphate synthetase 1

Biochem Biophys Res Commun. 2010 Feb 26;393(1):73-8. doi: 10.1016/j.bbrc.2010.01.081. Epub 2010 Jan 25.

Abstract

SIR2 protein, an NAD-dependent deacetylase, is localized to nucleus and is involved in life span extension by calorie restriction in yeast. In mammals, among the seven SIR2 homologues (SIRT1-7), SIRT3, 4, and 5 are localized to mitochondria. As SIRT5 mRNA levels in liver are increased by fasting, the physiological role of SIRT5 was investigated in liver of SIRT5-overexpressing transgenic (SIRT5 Tg) mice. We identified carbamoyl phosphate synthetase 1 (CPS1), a key enzyme of the urea cycle that catalyzes condensation of ammonia with bicarbonate to form carbamoyl phosphate, as a target of SIRT5 by two-dimensional electrophoresis comparing mitochondrial proteins in livers of SIRT5 Tg and wild-type mice. CPS1 protein was more deacetylated and activated in liver of SIRT5 Tg mice than in wild-type. In addition, urea production was upregulated in hepatocytes of SIRT5 Tg mice. These results agree with those of a previous study using SIRT5 knockout (KO) mice. Because ammonia generated during fasting is toxic, SIRT5 protein might play a protective role by converting ammonia to non-toxic urea through deacetylation and activation of CPS1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Amino Acid Sequence
  • Ammonia / metabolism*
  • Animals
  • Carbamoyl-Phosphate Synthase (Ammonia) / metabolism*
  • Enzyme Activation
  • Fasting / metabolism*
  • Hepatocytes / enzymology*
  • Hepatocytes / ultrastructure
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Mitochondria, Liver / enzymology
  • Molecular Sequence Data
  • Peptides / genetics
  • Peptides / metabolism
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / genetics
  • Sirtuins / biosynthesis*
  • Sirtuins / genetics
  • Up-Regulation
  • Urea / metabolism*

Substances

  • Peptides
  • RNA, Messenger
  • SIRT5 protein, mouse
  • Ammonia
  • Urea
  • Sirtuins
  • Carbamoyl-Phosphate Synthase (Ammonia)