Substrates and regulation mechanisms for the human mitochondrial Sirtuins Sirt3 and Sirt5
Substrates and regulation mechanisms for the human mitochondrial Sirtuins Sirt3 and Sirt5
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DOI：
10.1016/j.jmb.2008.07.048
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发表时间：
2008-10-10
影响因子：
5.6
通讯作者：
Steegborn, Clemens
中科院分区：
文献类型：
--
作者：
Schlicker, Christine;Gertz, Melanie;Steegborn, Clemens
烟酰胺腺嘌呤二核苷酸依赖性蛋白脱乙酰酶的Sirtuin家族的酶是核和胞质信号传导中的新兴关键参与者，而且也是线粒体调节和衰老中的关键参与者。哺乳动物线粒体含有三种Sirtuins，Sirt 3，Sirt 4和Sirt 5。已知Sirt 3和Sirt 4只有一种底物，到目前为止，还没有报道Sirt 5的靶点。在这里，我们描述了新的人类线粒体Sirtuin亚型Sirt 3和Sirt 5的底物的鉴定。我们表明，Sirt 3可以去乙酰化，从而激活线粒体基质中的中央代谢调节因子谷氨酸脱氢酶。此外，Sirt 3去乙酰化并激活异柠檬酸脱氢酶2，这是一种促进抗氧化剂再生并催化柠檬酸循环关键调节点的酶。因此，Sirt 3可以调节这个中心代谢循环的通量和倒空。我们进一步发现，N-和C-末端区域的Sirt 3调节其对谷氨酸脱氢酶和肽底物的活性，表明这些区域在底物识别和Sirtuin调节中的作用。与Sirt 3相反，Sirt 5不使测试的线粒体基质蛋白脱乙酰基。相反，它可以使细胞色素c脱乙酰化，细胞色素c是线粒体膜间隙的一种蛋白质，在氧化代谢以及细胞凋亡起始中具有中心功能。使用线粒体输入分析，我们发现，Sirt 5确实可以易位到线粒体膜间隙，但也到矩阵，表明本地化可能有助于Sirt 5的调节和底物选择。(C)2008爱思唯尔有限公司保留所有权利。
The enzymes of the Sirtuin family of nicotinamide-adenine-dinucleotide-dependent protein deacetylases are emerging key players in nuclear and cytosolic signaling, but also in mitochondrial regulation and aging. Mammalian mitochondria contain three Sirtuins, Sirt3, Sirt4, and Sirt5. Only one substrate is known for Sirt3 as well as for Sirt4, and up to now, no target for Sirt5 has been reported. Here, we describe the identification of novel Substrates for the human mitochondrial Sirtuin isoforms Sirt3 and Sirt5. We show that Sirt3 can deacetylate and thereby activate a central metabolic regulator in the mitochondrial matrix, glutamate dehydrogenase. Furthermore, Sirt3 deacetylates and activates isocitrate dehydrogenase 2, an enzyme that promotes regeneration of antioxidants and catalyzes a key regulation point of the citric acid cycle. Sirt3 thus can regulate flux and anapleurosis of this central metabolic cycle. We further find that the N- and C-terminal regions of Sirt3 regulate its activity against glutamate dehydrogenase and a peptide substrate, indicating roles for these regions in substrate recognition and Sirtuin regulation. Sirt5, in contrast to Sirt3, deacetylates none of the mitochondrial matrix proteins tested. Instead, it can deacetylate cytochrome c, a protein of the mitochondrial intermembrane space with a central function in oxidative metabolism, as well as apoptosis initiation. Using a mitochondrial import assay, we find that Sirt5 can indeed be translocated into the mitochondrial intermembrane space, but also into the matrix, indicating that localization might contribute to Sirt5 regulation and substrate selection. (C) 2008 Elsevier Ltd. All rights reserved.