A Novel Mechanism for SIRT1 Activators That Does Not Rely on the Chemical Moiety Immediately C-Terminal to the Acetyl-Lysine of the Substrate
SIRT1, an NAD<sup>+</sup>-dependent deacetylase, catalyzes the deacetylation of proteins coupled with the breakdown of NAD<sup>+</sup> into nicotinamide and 2′-O-acetyl-ADP-ribose (OAADPr). Selective SIRT1 activators have potential clinical applications in atherosclerosis, ac...
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MDPI AG
2022-04-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/27/9/2714 |
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| author | Nian-Da Yu Bing Wang Xin-Zhu Li Hao-Zhen Han Dongxiang Liu |
| author_facet | Nian-Da Yu Bing Wang Xin-Zhu Li Hao-Zhen Han Dongxiang Liu |
| author_sort | Nian-Da Yu |
| collection | DOAJ |
| description | SIRT1, an NAD<sup>+</sup>-dependent deacetylase, catalyzes the deacetylation of proteins coupled with the breakdown of NAD<sup>+</sup> into nicotinamide and 2′-O-acetyl-ADP-ribose (OAADPr). Selective SIRT1 activators have potential clinical applications in atherosclerosis, acute renal injury, and Alzheimer’s disease. Here, we found that the activity of the potent SIRT1 activator CWR is independent of the acetylated substrate. It adopts a novel mechanism to promote SIRT1 activity by covalently bonding to the anomeric C1′ carbon of the ribose ring in OAADPr. In addition, CWR is highly selective for SIRT1, with no effect on SIRT2, SIRT3, SIRT5, or SIRT6. The longer distance between the anomeric C1′ carbon of the ribose ring in OAADPr and Arg274 of SIRT1 (a conserved residue among sirtuins) than that between the anomeric C1′ carbon in OAADPr and the Arg of SIRT2, SIRT3, SIRT5, and SIRT6, should be responsible for the high selectivity of CWR for SIRT1. This was confirmed by site-directed mutagenesis of SIRT3. Consistent with the in vitro assays, the activator also reduced the acetylation levels of p53 in a concentration-dependent manner via SIRT1 in cells. Our study provides a new perspective for designing SIRT1 activators that does not rely on the chemical moiety immediately C-terminal to the acetyl-lysine of the substrate. |
| first_indexed | 2024-03-10T03:54:54Z |
| format | Article |
| id | doaj.art-b03ae118c4f64f1789b2dafe479902c5 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T03:54:54Z |
| publishDate | 2022-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-b03ae118c4f64f1789b2dafe479902c52023-11-23T08:48:36ZengMDPI AGMolecules1420-30492022-04-01279271410.3390/molecules27092714A Novel Mechanism for SIRT1 Activators That Does Not Rely on the Chemical Moiety Immediately C-Terminal to the Acetyl-Lysine of the SubstrateNian-Da Yu0Bing Wang1Xin-Zhu Li2Hao-Zhen Han3Dongxiang Liu4Center for Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, ChinaCenter for Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, ChinaSchool of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, ChinaCenter for Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, ChinaCenter for Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, ChinaSIRT1, an NAD<sup>+</sup>-dependent deacetylase, catalyzes the deacetylation of proteins coupled with the breakdown of NAD<sup>+</sup> into nicotinamide and 2′-O-acetyl-ADP-ribose (OAADPr). Selective SIRT1 activators have potential clinical applications in atherosclerosis, acute renal injury, and Alzheimer’s disease. Here, we found that the activity of the potent SIRT1 activator CWR is independent of the acetylated substrate. It adopts a novel mechanism to promote SIRT1 activity by covalently bonding to the anomeric C1′ carbon of the ribose ring in OAADPr. In addition, CWR is highly selective for SIRT1, with no effect on SIRT2, SIRT3, SIRT5, or SIRT6. The longer distance between the anomeric C1′ carbon of the ribose ring in OAADPr and Arg274 of SIRT1 (a conserved residue among sirtuins) than that between the anomeric C1′ carbon in OAADPr and the Arg of SIRT2, SIRT3, SIRT5, and SIRT6, should be responsible for the high selectivity of CWR for SIRT1. This was confirmed by site-directed mutagenesis of SIRT3. Consistent with the in vitro assays, the activator also reduced the acetylation levels of p53 in a concentration-dependent manner via SIRT1 in cells. Our study provides a new perspective for designing SIRT1 activators that does not rely on the chemical moiety immediately C-terminal to the acetyl-lysine of the substrate.https://www.mdpi.com/1420-3049/27/9/2714SIRT1activatorcovalent bond2′-O-acetyl-ADP-ribosedeacetylase |
| spellingShingle | Nian-Da Yu Bing Wang Xin-Zhu Li Hao-Zhen Han Dongxiang Liu A Novel Mechanism for SIRT1 Activators That Does Not Rely on the Chemical Moiety Immediately C-Terminal to the Acetyl-Lysine of the Substrate Molecules SIRT1 activator covalent bond 2′-O-acetyl-ADP-ribose deacetylase |
| title | A Novel Mechanism for SIRT1 Activators That Does Not Rely on the Chemical Moiety Immediately C-Terminal to the Acetyl-Lysine of the Substrate |
| title_full | A Novel Mechanism for SIRT1 Activators That Does Not Rely on the Chemical Moiety Immediately C-Terminal to the Acetyl-Lysine of the Substrate |
| title_fullStr | A Novel Mechanism for SIRT1 Activators That Does Not Rely on the Chemical Moiety Immediately C-Terminal to the Acetyl-Lysine of the Substrate |
| title_full_unstemmed | A Novel Mechanism for SIRT1 Activators That Does Not Rely on the Chemical Moiety Immediately C-Terminal to the Acetyl-Lysine of the Substrate |
| title_short | A Novel Mechanism for SIRT1 Activators That Does Not Rely on the Chemical Moiety Immediately C-Terminal to the Acetyl-Lysine of the Substrate |
| title_sort | novel mechanism for sirt1 activators that does not rely on the chemical moiety immediately c terminal to the acetyl lysine of the substrate |
| topic | SIRT1 activator covalent bond 2′-O-acetyl-ADP-ribose deacetylase |
| url | https://www.mdpi.com/1420-3049/27/9/2714 |
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