Overexpression of SIRT5 confirms its involvement in deacetylation and activation of carbamoyl phosphate synthetase 1
Overexpression of SIRT5 confirms its involvement in deacetylation and activation of carbamoyl phosphate synthetase 1
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DOI：
10.1016/j.bbrc.2010.01.081
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发表时间：
2010-02-26
影响因子：
3.1
通讯作者：
Inagaki, Nobuya
中科院分区：
文献类型：
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作者：
Ogura, Masahito;Nakamura, Yasuhiko;Inagaki, Nobuya
SIR2蛋白是一种烟酰胺腺嘌呤二核苷酸（NAD）依赖的去乙酰化酶，定位于细胞核，在酵母中参与由热量限制引起的寿命延长。在哺乳动物中，7种SIR2同源物（SIRT1 - 7）中，SIRT3、4和5定位于线粒体。由于禁食会使肝脏中SIRT5的信使核糖核酸（mRNA）水平升高，因此在过表达SIRT5的转基因（SIRT5 Tg）小鼠的肝脏中对SIRT5的生理作用进行了研究。我们通过比较SIRT5 Tg小鼠和野生型小鼠肝脏中的线粒体蛋白质的双向电泳，确定了氨甲酰磷酸合成酶I（CPS1）是SIRT5的一个作用靶点，CPS1是尿素循环中的一种关键酶，它催化氨与碳酸氢盐缩合形成氨甲酰磷酸。与野生型相比，SIRT5 Tg小鼠肝脏中的CPS1蛋白去乙酰化程度更高且更具活性。此外，SIRT5 Tg小鼠的肝细胞中尿素生成上调。这些结果与先前使用SIRT5基因敲除（KO）小鼠的研究结果一致。由于禁食期间产生的氨是有毒的，SIRT5蛋白可能通过使CPS1去乙酰化并激活它，从而将氨转化为无毒的尿素来发挥保护作用。（C）2010爱思唯尔公司。保留所有权利。
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 I (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. (C) 2010 Elsevier Inc. All rights reserved.