The DarT/DarG Toxin-Antitoxin ADP-Ribosylation System as a Novel Target for a Rational Design of Innovative Antimicrobial Strategies.
The DarT/DarG Toxin-Antitoxin ADP-Ribosylation System as a Novel Target for a Rational Design of Innovative Antimicrobial Strategies.
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DOI：
10.3390/pathogens12020240
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发表时间：
2023-02-02
期刊：
影响因子：
--
通讯作者：
Palazzo L
中科院分区：
文献类型：
--
作者：
Catara G;Caggiano R;Palazzo L
通过ADP-核糖单元的转移对细胞大分子进行化学修饰，称为ADP-核糖基化，是一种古老的稳态和应激反应控制系统。ADP-核糖基转移酶和ADP-核糖基水解酶在进化过程中高度保守，控制ADP-核糖基化信号传导和细胞反应。除了蛋白质之外，原核和真核转移酶都可以将ADP-核糖基化共价连接到核酸的不同构象，从而突出了古老的应激反应机制的进化保守性。在这里，我们报告了几个结构和功能方面的DNA ADP-核糖基化修饰控制的原型DRT和DarG对，这表明ADP-核糖基转移酶和水解酶活性，分别。DarT/DarG是在许多细菌病原体中保守的毒素-抗毒素系统，例如在结核分枝杆菌中，其调节对人类健康的两个临床上重要的过程，即生长控制和抗噬菌体应答。因此，通过选择性抑制剂对Dart-DarG系统进行化学调节可能代表了一种令人兴奋的策略，以解决对当前抗菌治疗的耐药性。
The chemical modification of cellular macromolecules by the transfer of ADP-ribose unit(s), known as ADP-ribosylation, is an ancient homeostatic and stress response control system. Highly conserved across the evolution, ADP-ribosyltransferases and ADP-ribosylhydrolases control ADP-ribosylation signalling and cellular responses. In addition to proteins, both prokaryotic and eukaryotic transferases can covalently link ADP-ribosylation to different conformations of nucleic acids, thus highlighting the evolutionary conservation of archaic stress response mechanisms. Here, we report several structural and functional aspects of DNA ADP-ribosylation modification controlled by the prototype DarT and DarG pair, which show ADP-ribosyltransferase and hydrolase activity, respectively. DarT/DarG is a toxin–antitoxin system conserved in many bacterial pathogens, for example in Mycobacterium tuberculosis, which regulates two clinically important processes for human health, namely, growth control and the anti-phage response. The chemical modulation of the DarT/DarG system by selective inhibitors may thus represent an exciting strategy to tackle resistance to current antimicrobial therapies.
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ADP-核糖基转移酶和 ADP-核糖基化系统的自然历史。
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Aravind L;Zhang D;de Souza RF;Anand S;Iyer LM
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