SIRT5 regulates the mitochondrial lysine succinylome and metabolic networks.
SIRT5 regulates the mitochondrial lysine succinylome and metabolic networks.
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SIRT5 调节线粒体赖氨酸琥珀酰组和代谢网络。
DOI：
10.1016/j.cmet.2013.11.013
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发表时间：
2013-12-03
期刊：
影响因子：
29
通讯作者：
Verdin E
中科院分区：
文献类型：
--
作者：
Rardin MJ;He W;Nishida Y;Newman JC;Carrico C;Danielson SR;Guo A;Gut P;Sahu AK;Li B;Uppala R;Fitch M;Riiff T;Zhu L;Zhou J;Mulhern D;Stevens RD;Ilkayeva OR;Newgard CB;Jacobson MP;Hellerstein M;Goetzman ES;Gibson BW;Verdin E
可逆的翻译后修饰正在成为线粒体蛋白质和代谢的关键调节因子。在这里，我们使用无标记的定量蛋白质组学方法来表征肝脏线粒体中的赖氨酸琥珀酰组及其由脱琥珀酰酶SIRT 5的调节。在Sirt 5 −/−动物中，共有1190个独特位点被确定为琥珀酰化，代表几种代谢途径（包括β-氧化和酮生成）的140种蛋白质中的386个位点被显著过度琥珀酰化。SIRT 5的缺失导致体内中链和长链酰基肉毒碱的积累和β-羟基丁酸酯的产生减少。此外，我们证明，SIRT 5调节琥珀酰化的限速生酮酶3-羟基-3-甲基戊二酰辅酶A合酶2（HMGCS 2）在体内和体外。最后，HMGCS 2上的高度琥珀酰化残基K83和K310突变为谷氨酸强烈抑制酶活性。总之，这些发现确立了SIRT 5作为线粒体中赖氨酸琥珀酰化的全局调节剂，并提出了通过HMGCS 2抑制生酮的机制。
Reversible posttranslational modifications are emerging as critical regulators of mitochondrial proteins and metabolism. Here, we use a label-free quantitative proteomic approach to characterize the lysine succinylome in liver mitochondria and its regulation by the desuccinylase SIRT5. A total of 1190 unique sites were identified as succinylated, and 386 sites across 140 proteins representing several metabolic pathways including β-oxidation and ketogenesis were significantly hypersuccinylated in Sirt5−/− animals. Loss of SIRT5 leads to accumulation of medium- and long-chain acylcarnitines and decreased β-hydroxybutyrate production in vivo. In addition, we demonstrate that SIRT5 regulates succinylation of the rate-limiting ketogenic enzyme 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2) both in vivo and in vitro. Finally, mutation of hypersuccinylated residues K83 and K310 on HMGCS2 to glutamic acid strongly inhibits enzymatic activity. Taken together, these findings establish SIRT5 as a global regulator of lysine succinylation in mitochondria and present a mechanism for inhibition of ketogenesis through HMGCS2.
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影响因子：
4.1
作者：
QUANT, PA;TUBBS, PK;BRAND, MD
通讯作者：
BRAND, MD
影响因子：
2.9
作者：
Skaff, D. Andrew;Miziorko, Henry M.
通讯作者：
Miziorko, Henry M.
影响因子：
5.8
作者：
Larkin, M. A.;Blackshields, G.;Higgins, D. G.
通讯作者：
Higgins, D. G.
代谢酶的乙酰化协调碳源利用和代谢通量
DOI：
10.1126/science.1179687
发表时间：
2010-02-19
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Wang Q;Zhang Y;Yang C;Xiong H;Lin Y;Yao J;Li H;Xie L;Zhao W;Yao Y;Ning ZB;Zeng R;Xiong Y;Guan KL;Zhao S;Zhao GP
通讯作者：
Zhao GP
影响因子：
7
作者：
Peng, Chao;Lu, Zhike;Zhao, Yingming
通讯作者：
Zhao, Yingming