结构生物学在 sirtuin 激活剂设计中的作用。

The role of structural biology in the design of sirtuin activators.

机构信息

Department of Drug Chemistry and Technologies, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy.

Department of Drug Chemistry and Technologies, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy; Pasteur Institute, Cenci-Bolognetti Foundation, Sapienza University of Rome, P. le A. Moro 5, 00185 Rome, Italy.

出版信息

Curr Opin Struct Biol. 2023 Oct;82:102666. doi: 10.1016/j.sbi.2023.102666. Epub 2023 Aug 4.

DOI:10.1016/j.sbi.2023.102666

PMID:37542908

Abstract

Sirtuins are NAD-dependent protein lysine deacylases and mono-ADP-ribosylases whose activity regulates different pathways, including DNA damage repair, cell survival and metabolism, reactive oxygen species (ROS) detoxification, inflammation, cardiac function, and neuronal signaling. Considering the beneficial effects of specific sirtuin isoforms on health and lifespan, the past two decades have seen a mounting interest in the development of sirtuin activators. The availability of enzyme-activator co-crystal structures has proven significant throughout the years for elucidating the mechanisms of action of activators and designing more potent and selective molecules. In this review, we highlight the most interesting examples of sirtuin activators and provide comprehensive coverage of the role that structural biology played in their discovery and characterization.

摘要

Sirtuins 是 NAD 依赖性蛋白赖氨酸去酰基酶和单 ADP-核糖基转移酶，其活性调节包括 DNA 损伤修复、细胞存活和代谢、活性氧 (ROS) 解毒、炎症、心脏功能和神经元信号在内的不同途径。鉴于特定的 Sirtuins 同工型对健康和寿命的有益影响，过去二十年中人们对 Sirtuins 激活剂的开发产生了浓厚的兴趣。多年来，酶-激活剂共晶结构的可用性对于阐明激活剂的作用机制和设计更有效和选择性的分子非常重要。在这篇综述中，我们重点介绍了最有趣的 Sirtuins 激活剂实例，并全面介绍了结构生物学在它们的发现和表征中所起的作用。