Seo Dong-Hyun, Huh Yang Hoon, Cheong Hae-Kap, Kim Eun-Hee, Lim Jong-Soo, Lee Min Jung, Lee Donghan, Ryu Kyoung-Seok
Ochang center, Korea Basic Science Institute, 162 Yeongudanji-Ro, Ochang-Eup, Cheongju-Si, Chungcheongbuk-Do 28119, South Korea.
KBSI School of Bioscience, University of Science and Technology, 162 Yeongudanji-Ro, Ochang-Eup, Cheongju-Si, Chungcheongbuk-Do 28119, South Korea.
JACS Au. 2024 May 7;4(7):2451-2455. doi: 10.1021/jacsau.4c00262. eCollection 2024 Jul 22.
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 O. 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 brain physoxia conditions, LMT may convert to MT, possibly interfering with tau fibrillation via disulfide bond formation.
亚甲蓝（MB）最近作为白亚甲硫鎓（LMT）双（氢甲磺酸盐）完成了一项治疗阿尔茨海默病的3期临床试验。在此，我们通过关注tau单体来研究MB抑制微管相关蛋白（tau）聚集的潜在机制。我们发现MB会导致二硫键形成，从而在tau蛋白的大片区域产生强烈的核磁共振化学位移扰动。MB的氧化形式，即亚甲硫鎓（MT），特异性地催化tau蛋白中半胱氨酸残基的氧化，直接利用O形成二硫键。这个过程独立于MT到LMT的氧化还原循环。此外，MT优先氧化富含赖氨酸的R2和R3结构域中的C291和C322。在脑缺氧条件下，LMT可能会转化为MT，可能通过二硫键形成干扰tau蛋白纤维化。
