A Novel Mechanism for SIRT1 Activators That Does Not Rely on the Chemical Moiety Immediately C-Terminal to the Acetyl-Lysine of the Substrate.
A Novel Mechanism for SIRT1 Activators That Does Not Rely on the Chemical Moiety Immediately C-Terminal to the Acetyl-Lysine of the Substrate.
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一种不依赖于底物乙酰赖氨酸直接c端化学片段的SIRT1激活剂的新机制。
DOI：
10.3390/molecules27092714
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发表时间：
2022-04-22
期刊：
影响因子：
4.6
通讯作者：
Liu, Dongxiang
中科院分区：
文献类型：
--
作者：
Yu, Nian-Da;Wang, Bing;Li, Xin-Zhu;Han, Hao-Zhen;Liu, Dongxiang
SIRT 1是一种NAD+依赖性脱乙酰酶，催化蛋白质的脱乙酰化，并将NAD+分解为烟酰胺和2′-O-乙酰基-ADP-核糖（OAADPr）。选择性SIRT 1激活剂在动脉粥样硬化、急性肾损伤和阿尔茨海默病中具有潜在的临床应用。在这里，我们发现有效的SIRT 1激活剂CWR的活性与乙酰化底物无关。它采用了一种新的机制，通过共价键合到OAADPr中核糖环的异头C1′碳来促进SIRT 1活性。此外，CWR对SIRT 1具有高度选择性，对SIRT 2、SIRT 3、SIRT 5或SIRT 6没有影响。OAADPr中核糖环的异头C1′碳与SIRT 1的Arg 274（sirtuins中的保守残基）之间的距离比OAADPr中异头C1′碳与SIRT 2、SIRT 3、SIRT 5和SIRT 6的Arg之间的距离更长，这应该是CWR对SIRT 1的高选择性的原因。这通过SIRT 3的定点诱变证实。与体外试验一致，激活剂还通过细胞中的SIRT 1以浓度依赖性方式降低p53的乙酰化水平。我们的研究为设计SIRT 1激活剂提供了一个新的视角，该激活剂不依赖于底物乙酰赖氨酸C末端的化学部分。
SIRT1, an NAD+-dependent deacetylase, catalyzes the deacetylation of proteins coupled with the breakdown of NAD+ 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.
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DOI：
10.18632/aging.100542
发表时间：
2013-03
期刊：
Aging
影响因子：
--
作者：
Lakshminarasimhan M;Rauh D;Schutkowski M;Steegborn C
通讯作者：
Steegborn C
DOI：
10.1126/science.1231097
发表时间：
2013-03-08
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Hubbard BP;Gomes AP;Dai H;Li J;Case AW;Considine T;Riera TV;Lee JE;E SY;Lamming DW;Pentelute BL;Schuman ER;Stevens LA;Ling AJ;Armour SM;Michan S;Zhao H;Jiang Y;Sweitzer SM;Blum CA;Disch JS;Ng PY;Howitz KT;Rolo AP;Hamuro Y;Moss J;Perni RB;Ellis JL;Vlasuk GP;Sinclair DA
通讯作者：
Sinclair DA
影响因子：
11.1
作者：
Park SJ;Ahmad F;Um JH;Brown AL;Xu X;Kang H;Ke H;Feng X;Ryall J;Philp A;Schenk S;Kim MK;Sartorelli V;Chung JH
通讯作者：
Chung JH
影响因子：
4.8
作者：
Pacholec, Michelle;Bleasdale, John E.;Ahn, Kay
通讯作者：
Ahn, Kay
DOI：
10.1107/s0907444913015448
发表时间：
2013-08-01
影响因子：
2.2
作者：
Giang Thi Tuyet Nguyen;Schaefer, Susanne;Steegborn, Clemens
通讯作者：
Steegborn, Clemens