Genistein, a natural product from soy, is a potent inhibitor of transthyretin amyloidosis
Genistein, a natural product from soy, is a potent inhibitor of transthyretin amyloidosis
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DOI：
10.1073/pnas.0501609102
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发表时间：
2005-10-11
影响因子：
11.1
通讯作者：
Kelly, JW
中科院分区：
文献类型：
--
作者：
Green, NS;Foss, TR;Kelly, JW
转甲状腺素(TTR)的错误折叠，包括限速四聚体解离和部分单体变性，足以使TTR错误组装成淀粉样蛋白和其他与三种淀粉样蛋白疾病相关的异常四级结构：老年性系统性淀粉样变性、家族性淀粉样多发性神经病和家族性淀粉样心肌病。小分子可以结合一个或两个未被占据的TTR甲状腺激素结合位点，比起解离的过渡态更能稳定天然四聚体，从而提高了四聚体解离的动力学障碍。在这里，我们证明了大豆中主要的异黄酮类天然产物金雀异黄素就是以这种方式起作用的，是一种极好的抑制转甲肾上腺素四聚体解离和淀粉样蛋白形成的药物，将酸介导的纤维形成减少到仅有TTR的10%。金雀异黄素还分别抑制最常见的家族性Anyloid多发性神经病和家族性Anyloid心肌病TTR：V30M和V1221突变的淀粉样蛋白的发生。金雀异黄素还可以在被认为导致人类淀粉样变缓慢的生理条件下抑制四聚体的解离。此外，与所有其他血浆蛋白相比，该天然产物与血浆中的TTR具有高度的选择性结合。等温滴定量热法测定表明染料木素与TTR以负协同作用结合(K-D_1=40 nm，K-D_2=1.4微米)。使用金雀异黄素等营养食品治疗孤儿疾病的好处包括已知的口服生物利用度和安全性数据。可以想象，一些患者可以从简单地增加大豆产品或补充剂的摄入量中受益。
The misfolding of transthyretin (TTR), including rate-limiting tetramer dissociation and partial monomer denaturation, is sufficient for TTR misassembly into amyloid and other abnormal quaternary structures associated with three amyloid diseases: senile systemic amyloidosis, familial amyloid polyneuropathy, and familial amyloid cardiomyopathy. Small molecules can bind to one or both of the unoccupied TTR thyroid hormone-binding sites, stabilizing the native tetramer more than the dissociative transition state, thereby raising the kinetic barrier for tetramer dissociation. Herein we demonstrate that genistein, the major isoflavone natural product in soy, works in this fashion and is an excellent inhibitor of transthyretin tetramer dissociation and amyloidogenesis, reducing acid-mediated fibril formation to < 10% of that exhibited by TTR alone. Genistein also inhibits the amyloidogenesis of the most common familial annyloid polyneuropathy and familial annyloid cardiomyopathy mutations in TTR: V30M and V1221, respectively. Genistein additionally inhibits tetramer dissociation under physiological conditions thought to lead to slow amyloidogenesis in humans. Furthermore, this natural product exhibits highly selective binding to TTR in plasma over all of the other plasma proteins. Isothermal titration calorimetry shows that genistein binds to TTR with negative cooperativity (K-d1 = 40 nM, K-d2 = 1.4 mu M). The benefits of using a nutraceutical such as genistein to treat orphan diseases such as the TTR amyloidoses include known oral bioavilability and safety data. It is conceivable that some patients could benefit from simply increasing their intake of soy products or supplements.