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Structural Insights into the Inhibition Site in the Phosphorylcholine Phosphatase Enzyme of Pseudomonas aeruginosa
Journal of Chemical Information and Modeling ( IF 5.6 ) Pub Date : 2022-06-07 , DOI: 10.1021/acs.jcim.2c00059
Daniel Bustos 1, 2 , Erix W Hernández-Rodríguez 2, 3 , Horacio Poblete 4, 5 , Jans Alzate-Morales 4 , Cecilia Challier 6 , Cristhian Boetsch 7 , Ariela Vergara-Jaque 4, 5 , Paola Beassoni 7
Affiliation  

Pseudomonas aeruginosa is a highly pathogenic Gram-negative microorganism associated with high mortality levels in burned or immunosuppressed patients or individuals affected by cystic fibrosis. Studies support a colonization mechanism whereby P. aeruginosa can breakdown the host cell membrane phospholipids through the sequential action of two enzymes: (I) hemolytic phospholipase C acting upon phosphatidylcholine or sphingomyelin to produce phosphorylcholine (Pcho) and (II) phosphorylcholine phosphatase (PchP) that hydrolyzes Pcho to generate choline and inorganic phosphate. This coordinated action provides the bacteria with carbon, nitrogen, and inorganic phosphate to support growth. Furthermore, PchP exhibits a distinctive inhibition mechanism by high substrate concentration. Here, we combine kinetic assays and computational approaches such as molecular docking, molecular dynamics, and free-energy calculations to describe the inhibitory site of PchP, which shares specific residues with the enzyme’s active site. Our study provides insights into a coupled inhibition mechanism by the substrate, allowing us to postulate that the integrity of the inhibition site is needed to the correct functioning of the active site. Our results allow us to gain a better understanding of PchP function and provide the basis for a rational drug design that might contribute to the treatment of infections caused by this important opportunistic pathogen.

中文翻译:

铜绿假单胞菌磷酸胆碱磷酸酶抑制位点的结构分析

铜绿假单胞菌是一种高致病性革兰氏阴性微生物,与烧伤或免疫抑制患者或受囊性纤维化影响的个体的高死亡率相关。研究支持一种定植机制,即铜绿假单胞菌可以通过两种酶的顺序作用分解宿主细胞膜磷脂:(I) 溶血性磷脂酶 C 作用于磷脂酰胆碱或鞘磷脂以产生磷酸胆碱 (Pcho) 和 (II) 磷酸胆碱磷酸酶 (PchP) 水解 Pcho 以产生胆碱和无机磷酸盐. 这种协同作用为细菌提供了碳、氮和无机磷酸盐以支持生长。此外,PchP 通过高底物浓度表现出独特的抑制机制。在这里,我们结合动力学分析和计算方法,如分子对接、分子动力学和自由能计算来描述 PchP 的抑制位点,它与酶的活性位点共享特定的残基。我们的研究提供了对底物耦合抑制机制的见解,允许我们假设活性位点的正确功能需要抑制位点的完整性。我们的结果使我们能够更好地了解 PchP 的功能,并为合理的药物设计提供基础,这可能有助于治疗由这种重要的机会性病原体引起的感染。
更新日期:2022-06-07
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