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首页> 外文会议>Meeting on Cell Signaling World: Signal Transduction Pathways as Therapeutic Targets >Modification of Proteins by Cyclopentenone Prostaglandins is Differentially Modulated by GSH in Vitro
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Modification of Proteins by Cyclopentenone Prostaglandins is Differentially Modulated by GSH in Vitro

机译：GSH体外差异调节环戊烯酮前列腺素对蛋白质的修饰

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Prostanoids with cyclopentenone structure (cyP) display a potent anti-inflammatory and antiproliferative activity. CyP are reactive compounds, which may modulate cellular functions by multiple mecha nisms, including the direct covalent modification of cysteine residues by Michael addition. This interaction displays selectivity since only a subset of cellular proteins is modified by cyP. Several factors have been proposed to influence the selectivity and/or extent of cyP addition to proteins, in cluding determinants related to protein and cyP structure, and levels of cellular thiols, such as glutathione (GSH). Here we have explored the ability of biotinylated cyP analogs to modify several recombinant pro teins in vitro, and the influence of GSH in these effects. We have observed that protein modification by cyP is protein- and cyP-selective. Under our conditions, biotinylated 15-deoxy-△~(12,14)-PGJ_2 (15d-PGJ_2-B) was more efficient than biotinylated PGA_1 (PGA_1-B) at forming adducts with com ponents of the transcription factors NF-κB and activator protein-1 (AP-1). However, both biotinylated cyP were nearly equipotent at modifying human GSTP1-1. Interestingly, the presence of GSH differentially mod ulated the formation of protein-cyP adducts. Under our conditions, GSH reduced the incorporation of cyP into GST, but improved their binding to p50, more intensely in the case of PGA_1-B. These results evidence the importance of GSH-cyP and/or GSH-protein interactions for the selec tivity of protein modification by cyP and suggest a complex role for GSH that may be related to its ability to prevent protein oxidation or induce conformational alterations. This may shed light on the factors involved in the pleiotropic effects of electrophiles with therapeutic potential.
机译：具有环戊烯酮结构（cyP）的类前列腺素显示出有效的抗炎和抗增殖活性。 CyP是反应性化合物，其可以通过多种机制调节细胞功能，包括通过迈克尔加成直接对半胱氨酸残基进行共价修饰。这种相互作用显示出选择性，因为只有一部分细胞蛋白被cyP修饰。已经提出了几种因素来影响向蛋白质中添加cyP的选择性和/或程度，包括与蛋白质和cyP结构有关的决定因素以及细胞硫醇的水平，例如谷胱甘肽（GSH）。在这里，我们探索了生物素化的cyP类似物在体外修饰几种重组蛋白的能力，以及GSH在这些作用中的影响。我们已经观察到，cyP对蛋白质的修饰是蛋白质和cyP选择性的。在我们的条件下，生物素化的15-脱氧-△〜（12,14）-PGJ_2（15d-PGJ_2-B）比生物素化的PGA_1（PGA_1-B）更有效地与转录因子NF-κB和激活蛋白1（AP-1）。但是，两种生物素化的cyP在修饰人GSTP1-1方面几乎相等。有趣的是，GSH的存在差异性地调节了蛋白质cyP加合物的形成。在我们的条件下，GSH减少了cyP掺入GST中，但在PGA_1-B的情况下，更强烈地增强了它们与p50的结合。这些结果证明了GSH-cyP和/或GSH-蛋白质相互作用对于通过cyP进行蛋白质修饰的选择性的重要性，并暗示了GSH的复杂作用，其可能与其预防蛋白质氧化或诱导构象改变的能力有关。这可能揭示了具有治疗潜力的亲电试剂的多效性作用所涉及的因素。

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