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, 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.
Ogura
Masahito
M
Department of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
Nakamura
Yasuhiko
Y
Tanaka
Daisuke
D
Zhuang
Xiaotong
X
Fujita
Yoshihito
Y
Obara
Akio
A
Hamasaki
Akihiro
A
Hosokawa
Masaya
M
Inagaki
Nobuya
N
D000107:Acetylation; D000595:Amino Acid Sequence; D000641:Ammonia / Q000378:metabolism*; D000818:Animals; D002222:Carbamoyl-Phosphate Synthase (Ammonia) / Q000378:metabolism*; D004789:Enzyme Activation; D005215:Fasting / Q000378:metabolism*; D022781:Hepatocytes / Q000201:enzymology* / Q000648:ultrastructure; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008930:Mitochondria, Liver / Q000201:enzymology; D008969:Molecular Sequence Data; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D037761:Sirtuins / Q000096:biosynthesis* / Q000235:genetics; D015854:Up-Regulation; D014508:Urea / Q000378:metabolism*
D010455:Peptides; D012333:RNA, Messenger; C542554:SIRT5 protein, mouse; D000641:Ammonia; D014508:Urea; D037761:Sirtuins; D002222:Carbamoyl-Phosphate Synthase (Ammonia)