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Molecular dynamics simulation of Toxin-Antitoxin (TA) system in Acinetobacter baumannii to explore the novel mechanism for inhibition of cell wall biosynthesis: Zeta Toxin as an effective therapeutic target
Journal of Cellular Biochemistry ( IF 4 ) Pub Date : 2021-08-26 , DOI: 10.1002/jcb.30137
Alagesan Karthika 1 , Balajee Ramachandran 1 , Jeyarajpandian Chitra 2 , Dhamodharan Prabhu 1 , Sundaraj Rajamanikandan 1 , Malaisamy Veerapandiyan 1 , Jeyaraman Jeyakanthan 1
Affiliation  

The majority of bacteria and archaea contains Toxin-Antitoxin system (TA) that codes for the stable Toxin and unstable Antitoxin components forming a complex. The Antitoxin inhibits the catalytic activities of the Toxin. In general, the Antitoxin will be degraded by the proteases leading to the Toxin activation that subsequently targets essential cellular processes, including transcription, translation, replication, cell division, and cell wall biosynthesis. The Zeta Toxin-Epsilon Antitoxin system in ESKAPE pathogen stabilizes the resistance plasmid and promotes pathogenicity. The known TA system in Acinetobacter baumannii are known to be involved in the replication and translation, however, the mechanism of Zeta Toxin-Epsilon Antitoxin in cell wall biosynthesis remains unknown. In the present study, molecular docking and molecular dynamic (MD) simulations were employed to demonstrate whether Zeta Toxin can impair cell wall synthesis in A. baumannii. Further, the degradation mechanism of Antitoxin in the presence and absence of adenosine triphosphate (ATP) molecules are explained through MD simulation. The result reveals that the cleavage of Antitoxin could be possible with the presence of ATP by displaying its response from 20 ns, whereas the Zeta Toxin/Epsilon was unstable after 90 ns. The obtained results demonstrate that Zeta Toxin is “temporarily favorable” for ATP to undergo phosphorylation at UNAG kinase through the substrate tunneling process. The study further evidenced that phosphorylated UNAG prevents the binding of MurA, the enzyme that catalyzes the initial step of bacterial peptidoglycan biosynthesis. Therefore, the present study explores the binding mechanism of Zeta Toxin/Epsilon Antitoxin, which could be beneficial for preventing cell wall biosynthesis as well as for unveiling the alternative treatment options to antibiotics.

中文翻译:

鲍曼不动杆菌毒素-抗毒素(TA)系统的分子动力学模拟探索抑制细胞壁生物合成的新机制:Zeta毒素作为有效的治疗靶点

大多数细菌和古细菌都含有毒素-抗毒素系统 (TA),它编码稳定的毒素和不稳定的抗毒素成分,形成复合物。抗毒素抑制毒素的催化活性。一般而言,抗毒素将被蛋白酶降解,导致毒素活化,随后靶向基本细胞过程,包括转录、翻译、复制、细胞分裂和细胞壁生物合成。ESKAPE 病原体中的 Zeta Toxin-Epsilon 抗毒素系统可稳定抗性质粒并促进致病性。鲍曼不动杆菌中已知的 TA 系统已知参与复制和翻译,然而,Zeta Toxin-Epsilon Antitoxin 在细胞壁生物合成中的机制仍然未知。在本研究中,采用分子对接和分子动力学 (MD) 模拟来证明 Zeta 毒素是否会损害鲍曼不动杆菌的细胞壁合成. 此外,通过MD模拟解释了在存在和不存在三磷酸腺苷(ATP)分子的情况下抗毒素的降解机制。结果表明,在 ATP 存在的情况下,抗毒素的裂解可能会在 20 ns 后显示其响应,而 Zeta 毒素/Epsilon 在 90 ns 后不稳定。获得的结果表明,Zeta 毒素“暂时有利于”ATP 通过底物隧道过程在 UNAG 激酶处进行磷酸化。该研究进一步证明磷酸化的 UNAG 阻止了 MurA 的结合,MurA 是催化细菌肽聚糖生物合成初始步骤的酶。因此,本研究探讨了 Zeta Toxin/Epsilon Antitoxin 的结合机制,
更新日期:2021-08-26
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