Mechanism of Methylene Blue Inducing the Disulfide Bond Formation of Tubulin-Associated Unit Proteins,JACS Au

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Mechanism of Methylene Blue Inducing the Disulfide Bond Formation of Tubulin-Associated Unit Proteins
JACS Au ( IF 8.5 ) Pub Date : 2024-05-07 , DOI: 10.1021/jacsau.4c00262
Dong-Hyun Seo _{1,

2} , Yang Hoon Huh ₁ , Hae-Kap Cheong ₁ , Eun-Hee Kim ₁ , Jong-Soo Lim ₃ , Min Jung Lee ₄ , Donghan Lee ₁ , Kyoung-Seok Ryu _{1,

2}

Affiliation

Methylene blue (MB) has recently completed a Phase-3 clinical trial as leuco-methylthioninium (LMT) bis(hydromethanesulfonate) for treating Alzheimer’s disease. Herein, we investigated the mechanism underlying the MB inhibition of tubulin-associated unit (tau) aggregation by focusing on tau monomers. We found that MB causes disulfide bond formation, resulting in strong nuclear magnetic resonance chemical shift perturbations in a large area of tau proteins. The oxidized form of MB, namely methylthioninium (MT⁺), specifically catalyzed the oxidation of cysteine residues in tau proteins to form disulfide bonds directly using O₂. This process is independent of the MT⁺-to-LMT redox cycle. Moreover, MT⁺ preferentially oxidized C291 and C322 in the lysine-rich R2 and R3 domains. Under in vivo brain physoxia conditions, LMT may convert to MT⁺, possibly interfering with tau fibrillation via disulfide bond formation.

中文翻译：

亚甲基蓝诱导微管蛋白相关单元蛋白二硫键形成的机制

亚甲蓝 (MB) 最近完成了一项作为无色甲基硫鎓 (LMT) 双（氢甲磺酸盐）治疗阿尔茨海默病的 3 期临床试验。在此，我们通过关注 tau 单体，研究了 MB 抑制微管蛋白相关单位 (tau) 聚集的机制。我们发现MB引起二硫键形成，导致大面积的tau蛋白产生强烈的核磁共振化学位移扰动。 MB的氧化形式，即甲硫鎓(MT ⁺ )，直接利用O ₂特异性催化tau蛋白中半胱氨酸残基的氧化形成二硫键。该过程独立于 MT ⁺至 LMT 氧化还原循环。此外，MT ⁺优先氧化富含赖氨酸的 R2 和 R3 结构域中的 C291 和 C322。在体内脑缺氧条件下，LMT 可能转化为 MT ⁺ ，可能通过二硫键的形成干扰 tau 纤维颤动。

更新日期：2024-05-07

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