长寿蛋白SIRT6在衰老和代谢中作用的研究进展

doi:10.3969/j.issn.1674-8115.2024.11.011

上海交通大学学报（医学版） ›› 2024, Vol. 44 ›› Issue (11): 1439-1446.doi: 10.3969/j.issn.1674-8115.2024.11.011

长寿蛋白SIRT6在衰老和代谢中作用的研究进展

刘永慧¹(), 唐莉¹, 梁泰刚¹, 张健²(), 冯丽²()

^1.山西医科大学药学院，太原 030001
^2.上海交通大学医学院药物化学与生物信息中心，上海 200025

收稿日期:2024-06-05 接受日期:2024-06-11 出版日期:2024-11-28 发布日期:2024-11-28
通讯作者: 张　健，电子信箱：jian.zhang@sjtu.deu.cn。^＃为共同通信作者。
冯　丽，电子信箱：fengli2020@sjtu.edu.cn
作者简介:刘永慧（1999—），女，硕士生；电子信箱：QLiuYongHui@163.com。
基金资助:
国家重点研发计划(2023YFF1205103)

Research progress in the role of SIRT6 in aging and metabolism

LIU Yonghui¹(), TANG Li¹, LIANG Taigang¹, ZHANG Jian²(), FENG Li²()

^1.School of Pharmacy, Shanxi Medical University, Taiyuan 030001, China
^2.Medicinal Chemistry and Bioinformatics Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China

Received:2024-06-05 Accepted:2024-06-11 Online:2024-11-28 Published:2024-11-28
Contact: ZHANG Jian, E-mail: jian.zhang@sjtu.edu.cn.
FENG Li, E-mail: fengli2020@sjtu.edu.cn
Supported by:
National Key Research and Development Program of China(2023YFF1205103)

摘要/Abstract

摘要：

SIRT6是组蛋白去乙酰化酶第三家族长寿蛋白中的一员，具备依赖于烟酰胺腺嘌呤二核苷酸的脱酰基酶活性和单ADP核糖基转移酶活性。SIRT6主要位于细胞核内，可通过核心调控基因组稳定性和相关基因表达，参与控制机体能量代谢和衰老在内的关键过程。鉴于其在维持细胞稳态和机体健康中的关键作用，SIRT6作为潜在的药物靶点引起人们对其靶向调节剂开发广泛的研究兴趣。药物激动长寿蛋白的活性可能治疗与年龄相关的疾病，如衰老、代谢综合征、炎症和生殖健康等。该文综述了SIRT6的结构特征、酶活性、生物学功能，以及SIRT6激动剂的作用机制、药理活性和临床应用。

关键词: SIRT6, 去乙酰化酶活, 衰老, 代谢, 炎症, 药物发现

Abstract:

SIRT6, a member of the sirtuin family of histone deacetylases, belongs to the class Ⅲ longevity proteins and exhibits NAD⁺-dependent deacetylase and mono-ADP-ribosyltransferase activities. SIRT6 is primarily located in the cell nucleus and plays a pivotal role in regulating genomic stability and relative gene expression, participating in the control of key processes such as energy metabolism and aging. Given its crucial role in maintaining cellular homeostasis and organismal health, SIRT6 has emerged as a potential therapeutic target, sparking significant research interest in the development of targeted modulators. Activating the longevity protein with drugs may provide therapeutic strategies for age-associated diseases, including aging, metabolic syndrome, inflammation, and reproductive health issues. The review elaborates the structural characteristics, enzymatic activities, and biological functions of SIRT6, as well as the mechanisms of action, pharmacological activities, and clinical applications of various SIRT6 activators.

Key words: SIRT6, catalytic activity, aging, metabolism, inflammation, drug discovery

中图分类号:

R966

刘永慧, 唐莉, 梁泰刚, 张健, 冯丽. 长寿蛋白SIRT6在衰老和代谢中作用的研究进展[J]. 上海交通大学学报（医学版）, 2024, 44(11): 1439-1446.

LIU Yonghui, TANG Li, LIANG Taigang, ZHANG Jian, FENG Li. Research progress in the role of SIRT6 in aging and metabolism[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2024, 44(11): 1439-1446.

图/表 3

图1 人源SIRT6蛋白的二级结构Note： The structural composition of SIRT6 is basically divided into Rossmann fold structure, small structural domains (including the zinc finger module), C-terminal extension (CTE) and N-terminal extension (NTE). SIRT6 is shown as a purple cartoon structure with lake blue stick structures for NAD+ and green for ADP ribose.

Fig 1 Secondary structure of the human protein SIRT6

图2 SIRT6催化去酰化的分子机制Note： NAD+ acts as a cofactor to assist SIRT6 in removing acylation groups from substrate lysine residues, resulting in the generation of NAM, ADP ribose, and the deacetylated product.

Fig 2 Mechanism of SIRT6 catalyzing deacylation

图3 SIRT6 激动剂的化学结构和结合模式Note： A. Chemical structures of SIRT6 agonist, MDL-800, MDL-801, and UBCS039. B. The binding modes of MDL-801 or UBCS039 with SIRT6. MDL-801 and UBCS039 are shown in green and blue sticks, respectively.

Fig 3 Structure and binding modes of SIRT6 activators

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长寿蛋白SIRT6在衰老和代谢中作用的研究进展

Research progress in the role of SIRT6 in aging and metabolism

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