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

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, th...

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Bibliographic Details
Published in:Biochemical and biophysical research communications 2010-02, Vol.393 (1), p.73-78
Main Authors: Ogura, Masahito, Nakamura, Yasuhiko, Tanaka, Daisuke, Zhuang, Xiaotong, Fujita, Yoshihito, Obara, Akio, Hamasaki, Akihiro, Hosokawa, Masaya, Inagaki, Nobuya
Format: Article
Language:English
Subjects:
Acetylation
Amino Acid Sequence
Ammonia - metabolism
Animals
Carbamoyl-Phosphate Synthase (Ammonia) - metabolism
Enzyme Activation
Fasting - metabolism
Hepatocytes - enzymology
Hepatocytes - ultrastructure
Liver
Mice
Mice, Knockout
Mice, Transgenic
Mitochondria
Mitochondria, Liver - enzymology
Molecular Sequence Data
Peptides - genetics
Peptides - metabolism
RNA, Messenger - biosynthesis
RNA, Messenger - genetics
SIRT5
Sirtuins - biosynthesis
Sirtuins - genetics
Up-Regulation
Urea - metabolism
Urea cycle
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Summary: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.
ISSN:0006-291X
1090-2104
DOI:10.1016/j.bbrc.2010.01.081