1 Departamento de Bioquímica, Facultad de Medicina, Universidad de la República , Montevideo, Uruguay .
2 Center for Free Radical and Biomedical Research , Universidad de la República, Montevideo, Uruguay .
Antioxid Redox Signal. 2018 Feb 20;28(6):487-504. doi: 10.1089/ars.2017.7074. Epub 2017 May 10.
Mycothiol (MSH, AcCys-GlcN-Ins) is the main low-molecular weight (LMW) thiol of most Actinomycetes, including the human pathogen Mycobacterium tuberculosis that affects millions of people worldwide. Strains with decreased MSH content show increased susceptibilities to hydroperoxides and electrophilic compounds. In M. tuberculosis, MSH modulates the response to several antituberculosis drugs. Enzymatic routes involving MSH could provide clues for specific drug design. Recent Advances: Physicochemical data argue against a rapid, nonenzymatic reaction of MSH with oxidants, disulfides, or electrophiles. Moreover, exposure of the bacteria to high concentrations of two-electron oxidants resulted in protein mycothiolation. The recently described glutaredoxin-like protein mycoredoxin-1 (Mrx-1) provides a route for catalytic reduction of mycothiolated proteins, protecting critical cysteines from irreversible oxidation. The description of MSH/Mrx-1-dependent activities of peroxidases helped to explain the higher susceptibility to oxidants observed in Actinomycetes lacking MSH. Moreover, the first mycothiol-S-transferase, member of the DinB superfamily of proteins, was described. In Corynebacterium, both the MSH/Mrx-1 and the thioredoxin pathways reduce methionine sulfoxide reductase A. A novel tool for in vivo imaging of the MSH/mycothiol disulfide (MSSM) status allows following changes in the mycothiol redox state during macrophage infection and its relationship with antibiotic sensitivity.
Redundancy of MSH with other LMW thiols is starting to be unraveled and could help to rationalize the differences in the reported importance of MSH synthesis observed in vitro versus in animal infection models.
Future work should be directed to establish the structural bases of the specificity of MSH-dependent enzymes, thus facilitating drug developments. Antioxid. Redox Signal. 28, 487-504.
巯基乙胺（MSH，AcCys-GlcN-Ins）是大多数放线菌的主要低分子量（LMW）巯基，包括影响全球数百万人的人类病原体结核分枝杆菌。MSH 含量降低的菌株对过氧化物和亲电化合物的敏感性增加。在结核分枝杆菌中，MSH 调节对几种抗结核药物的反应。涉及 MSH 的酶途径可以为特定药物设计提供线索。最新进展：物理化学数据表明 MSH 与氧化剂、二硫化物或亲电试剂的快速非酶反应是不可能的。此外，将细菌暴露于高浓度的两电子氧化剂会导致蛋白质巯基化。最近描述的谷氧还蛋白样蛋白 mycoredoxin-1（Mrx-1）为催化还原巯基化蛋白提供了一条途径，保护关键半胱氨酸免受不可逆氧化。描述 MSH/Mrx-1 依赖性过氧化物酶活性有助于解释在缺乏 MSH 的放线菌中观察到的对氧化剂更高的敏感性。此外，描述了第一个巯基乙胺-S-转移酶，DinB 超家族蛋白的成员。在棒状杆菌中，MSH/Mrx-1 和硫氧还蛋白途径都还原甲硫氨酸亚砜还原酶 A。一种新的工具用于体内成像 MSH/巯基乙胺二硫化物（MSSM）状态，可以在巨噬细胞感染过程中跟踪巯基乙胺还原状态的变化及其与抗生素敏感性的关系。
MSH 与其他 LMW 巯基的冗余性开始被揭示，这有助于解释在体外和动物感染模型中观察到的 MSH 合成重要性的差异。
未来的工作应该致力于确定 MSH 依赖性酶的特异性的结构基础，从而促进药物的开发。抗氧化。氧化还原信号。28,487-504。
