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      A small molecule activator of SIRT3 promotes deacetylation and activation of manganese superoxide dismutase.

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          Abstract

          The modulation of protein acetylation network is a promising strategy for life span extension and disease treatment (Sabari et al., 2016; Giblin et al., 2014) [1,2]. A variety of small molecules have been developed to target deacetylases, but extremely few of these molecules are capable of activating the mitochondrial NAD-dependent deacetylase sirtuin-3 (SIRT3) (Gertz and Steegborn, 2016; Scholz et al., 2015) [3,4]. Manganese superoxide dismutase (MnSOD) is the major superoxide scavenger in mitochondria, whose activity is regulated by SIRT3-mediated deacetylation, particularly at the Lys68 site (Chen et al., 2011) [5]. To investigate the influence of Lys68 acetylation on MnSOD activity, we produced a mutant MnSOD protein-bearing N-acetyllysine (AcK) at its Lys68 position through the genetic code expansion approach. We solved the crystal structure of this acetylated MnSOD (MnSODK68AcK), thus revealing the structural and electrostatic basis for the significant activity decrease upon Lys68 acetylation. On the basis of an assay we developed for the SIRT3-mediated deacetylation of MnSODK68AcK, we identified a novel SIRT3 activator, 7-hydroxy-3-(4'-methoxyphenyl) coumarin (C12), which binds to SIRT3 with high affinity and can promote the deacetylation and activation of MnSOD. C12 adds to the current repertoire of extremely few SIRT3 activators, which are potentially valuable for treating a wide array of diseases via modulating the cellular acetylome.

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          Author and article information

          Journal
          Free Radic. Biol. Med.
          Free radical biology & medicine
          Elsevier BV
          1873-4596
          0891-5849
          Nov 2017
          : 112
          Affiliations
          [1 ] State Key Laboratory of Natural and Biomimetic Drugs, Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China.
          [2 ] Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences, Chaoyang District, Beijing 100101, China; State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, Inner Mongolia University, Huhhot, 010021,China.
          [3 ] Department of Physics, Jilin University, Changchun 130012, China.
          [4 ] Guangzhou Institute of Chemistry, Chinese Academy of Sciences, Tianhe District, Guangzhou 510650, China.
          [5 ] Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences, Chaoyang District, Beijing 100101, China.
          [6 ] School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230026, China.
          [7 ] Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin 300308, China.
          [8 ] Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou 350002, China. Electronic address: wzhuang@fjirsm.ac.cn.
          [9 ] State Key Laboratory of Natural and Biomimetic Drugs, Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China. Electronic address: xqing@bjmu.edu.cn.
          [10 ] Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences, Chaoyang District, Beijing 100101, China. Electronic address: jwang@ibp.ac.cn.
          Article
          S0891-5849(17)30684-6
          10.1016/j.freeradbiomed.2017.07.012
          28711502
          d5d5ca12-ad2a-4083-9851-0c2043e19b9b
          History

          Acetylation,Electrostatic potential,Superoxide,SIRT3,MnSOD
          Acetylation, Electrostatic potential, Superoxide, SIRT3, MnSOD

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