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Oxidation of cathepsin S by major chemicals of cigarette smoke.
Free Radical Biology and Medicine ( IF 7.4 ) Pub Date : 2020-02-19 , DOI: 10.1016/j.freeradbiomed.2020.02.013
Mylène Wartenberg 1 , Pierre-Marie Andrault 1 , Ahlame Saidi 1 , Paul Bigot 1 , Lydie Nadal-Desbarats 2 , Fabien Lecaille 1 , Gilles Lalmanach 1
Affiliation  

Lung cysteine cathepsin S (CatS) that is a potent elastase plays a deleterious role in alveolar remodeling during smoke-induced emphysema. Despite the presence of a reactive nucleophilic cysteine (Cys25) within its active site, most of its elastinolytic activity is preserved after exposure to cigarette smoke extract (CSE), a major source of sulfhydryl oxidants. This result led us to decipher CatS resistance to major and representative CSE oxidants: hydrogen peroxide, formaldehyde, acrolein and peroxynitrite. CatS was inactivated by hydrogen peroxide, peroxynitrite and acrolein in a time- and dose-dependent manner, while formaldehyde was a weaker oxidant. Hydrogen peroxide, but not CSE, formaldehyde, and peroxynitrite impaired the autocatalytic maturation of pro-CatS, whereas acrolein prevented the formation of mature CatS without hindering the initial step of the two-step autocatalytic process. Far-UV CD spectra analysis supported that oxidation by CSE and hydrogen peroxide did not led to a structural alteration of CatS, despite a notable increase of protein carbonylation, a major hallmark of oxidative damage. Evaluation of the oxidation status of Cys25 by specific biotinylated redox sensing probes suggested the formation of sulfenic acid followed by a slower conversion to sulfinic acid after incubation with hydrogen peroxide. Addition of reducing reagents (dithiothreitol, glutathione and N-acetyl cysteine) led to a partial recovery of CatS activity following incubation with CSE, hydrogen peroxide and peroxynitrite. Current results provide some mechanistic evidence of CatS stability and activity in the presence of CSE, supporting its harmful contribution to the pathophysiology of emphysema.

中文翻译:

香烟烟雾中的主要化学物质氧化组织蛋白酶S。

肺半胱氨酸组织蛋白酶S(CatS)是一种有效的弹性蛋白酶,在烟雾诱发的肺气肿过程中对肺泡重塑起有害作用。尽管在其活性位点中存在反应性亲核半胱氨酸(Cys25),但在暴露于香烟烟雾提取物(CSE)(巯基氧化剂的主要来源)后,大部分弹性蛋白酶活性得以保留。该结果使我们破译了CatS对主要和代表性的CSE氧化剂:过氧化氢,甲醛,丙烯醛和过亚硝酸盐的抗性。过氧化氢,过氧亚硝酸盐和丙烯醛以时间和剂量依赖的方式使CatS失活,而甲醛是一种较弱的氧化剂。过氧化氢会破坏pro-CatS的自催化成熟,但不会破坏CSE,甲醛和过氧亚硝酸盐,而丙烯醛阻止了成熟的CatS的形成,而没有阻碍两步自催化过程的起始步骤。远紫外线CD光谱分析支持CSE和过氧化氢的氧化不会导致CatS的结构改变,尽管蛋白质羰基化显着增加,这是氧化损伤的主要标志。通过特定的生物素化氧化还原传感探针对Cys25氧化状态的评估表明,与过氧化氢孵育后,形成了亚磺酸,随后转化为亚磺酸的速度较慢。与CSE,过氧化氢和过氧亚硝酸盐一起孵育后,添加还原剂(二硫苏糖醇,谷胱甘肽和N-乙酰基半胱氨酸)可部分恢复CatS活性。
更新日期:2020-02-20
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