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Leveraging an enzyme/artificial substrate system to enhance cellular persulfides and mitigate neuroinflammation
Chemical Science ( IF 8.4 ) Pub Date : 2021-08-24 , DOI: 10.1039/d1sc03828a Prerona Bora 1 , Suman Manna 1 , Mrutyunjay A Nair 1 , Rupali R M Sathe 2 , Shubham Singh 2 , Venkata Sai Sreyas Adury 1 , Kavya Gupta 3 , Arnab Mukherjee 1 , Deepak K Saini 3 , Siddhesh S Kamat 2 , Amrita B Hazra 1, 2 , Harinath Chakrapani 1
Chemical Science ( IF 8.4 ) Pub Date : 2021-08-24 , DOI: 10.1039/d1sc03828a Prerona Bora 1 , Suman Manna 1 , Mrutyunjay A Nair 1 , Rupali R M Sathe 2 , Shubham Singh 2 , Venkata Sai Sreyas Adury 1 , Kavya Gupta 3 , Arnab Mukherjee 1 , Deepak K Saini 3 , Siddhesh S Kamat 2 , Amrita B Hazra 1, 2 , Harinath Chakrapani 1
Affiliation
Persulfides and polysulfides, collectively known as the sulfane sulfur pool along with hydrogen sulfide (H2S), play a central role in cellular physiology and disease. Exogenously enhancing these species in cells is an emerging therapeutic paradigm for mitigating oxidative stress and inflammation that are associated with several diseases. In this study, we present a unique approach of using the cell's own enzyme machinery coupled with an array of artificial substrates to enhance the cellular sulfane sulfur pool. We report the synthesis and validation of artificial/unnatural substrates specific for 3-mercaptopyruvate sulfurtransferase (3-MST), an important enzyme that contributes to sulfur trafficking in cells. We demonstrate that these artificial substrates generate persulfides in vitro as well as mediate sulfur transfer to low molecular weight thiols and to cysteine-containing proteins. A nearly 100-fold difference in the rates of H2S production for the various substrates is observed supporting the tunability of persulfide generation by the 3-MST enzyme/artificial substrate system. Next, we show that the substrate 1a permeates cells and is selectively turned over by 3-MST to generate 3-MST-persulfide, which protects against reactive oxygen species-induced lethality. Lastly, in a mouse model, 1a is found to significantly mitigate neuroinflammation in the brain tissue. Together, the approach that we have developed allows for the on-demand generation of persulfides in vitro and in vivo using a range of shelf-stable, artificial substrates of 3-MST, while opening up possibilities of harnessing these molecules for therapeutic applications.
中文翻译:
利用酶/人工底物系统增强细胞过硫化物并减轻神经炎症
过硫化物和多硫化物,与硫化氢 (H 2 S)一起统称为硫烷硫库,在细胞生理学和疾病中起着核心作用。外源性增强细胞中的这些物种是一种新兴的治疗范例,用于减轻与多种疾病相关的氧化应激和炎症。在这项研究中,我们提出了一种独特的方法,即使用细胞自身的酶机制与一系列人工底物相结合来增强细胞中的硫烷硫池。我们报告了对 3-巯基丙酮酸硫转移酶 (3-MST) 具有特异性的人工/非天然底物的合成和验证,这是一种有助于细胞中硫运输的重要酶。我们证明这些人造底物在体外产生过硫化物以及介导硫转移到低分子量硫醇和含半胱氨酸的蛋白质。观察到各种底物的 H 2 S 产生速率有近 100 倍的差异,支持 3-MST 酶/人工底物系统产生过硫化物的可调性。接下来,我们展示了底物1a渗透细胞并被 3-MST 选择性翻转以生成 3-MST-过硫化物,从而防止活性氧诱导的致死率。最后,在小鼠模型中,发现1a可显着减轻脑组织中的神经炎症。总之,我们开发的方法允许在体外和体内按需生成过硫化物 使用一系列货架稳定的 3-MST 人造基质,同时开辟了利用这些分子进行治疗应用的可能性。
更新日期:2021-09-15
中文翻译:
利用酶/人工底物系统增强细胞过硫化物并减轻神经炎症
过硫化物和多硫化物,与硫化氢 (H 2 S)一起统称为硫烷硫库,在细胞生理学和疾病中起着核心作用。外源性增强细胞中的这些物种是一种新兴的治疗范例,用于减轻与多种疾病相关的氧化应激和炎症。在这项研究中,我们提出了一种独特的方法,即使用细胞自身的酶机制与一系列人工底物相结合来增强细胞中的硫烷硫池。我们报告了对 3-巯基丙酮酸硫转移酶 (3-MST) 具有特异性的人工/非天然底物的合成和验证,这是一种有助于细胞中硫运输的重要酶。我们证明这些人造底物在体外产生过硫化物以及介导硫转移到低分子量硫醇和含半胱氨酸的蛋白质。观察到各种底物的 H 2 S 产生速率有近 100 倍的差异,支持 3-MST 酶/人工底物系统产生过硫化物的可调性。接下来,我们展示了底物1a渗透细胞并被 3-MST 选择性翻转以生成 3-MST-过硫化物,从而防止活性氧诱导的致死率。最后,在小鼠模型中,发现1a可显着减轻脑组织中的神经炎症。总之,我们开发的方法允许在体外和体内按需生成过硫化物 使用一系列货架稳定的 3-MST 人造基质,同时开辟了利用这些分子进行治疗应用的可能性。