Self-Assembly of Artificial Sweetener Aspartame Yields Amyloid-like Cytotoxic Nanostructures
Self-Assembly of Artificial Sweetener Aspartame Yields Amyloid-like Cytotoxic Nanostructures
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DOI：
10.1021/acsnano.9b02284
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发表时间：
2019-05-01
期刊：
影响因子：
17.1
通讯作者：
Kar, Karunakar
中科院分区：
文献类型：
--
作者：
Anand, Bibin Gnanadhason;Prajapati, Kailash Prasad;Kar, Karunakar
最近的报道揭示了单一芳香族代谢物进行自组装并形成淀粉样蛋白性质的纳米结构的内在倾向。因此，确定是否甜，普遍消费的人工甜味剂，是固有的聚集倾向成为一个重要的研究领域。尽管关于西洛沙姆相关副作用的报告描述了多种代谢紊乱，但对这种破坏性作用的机械理解在很大程度上是神秘的。由于芳香性（一种聚集促进因子）是甜菊糖化学的固有特性，因此了解甜菊糖是否可以进行自缔合以及这种特性是否会导致对生物系统的任何细胞毒性是很重要的。我们的研究发现，在模拟的生理条件下，甜菜碱分子经历自发的自组装过程，产生规则的β-折叠样的淀粉样蛋白性质的细胞毒性纳米纤维。发现所得的芝麻原纤维触发淀粉样蛋白交叉播种，并成为球状蛋白、A β肽和芳香族代谢物的毒性聚集陷阱，其将天然结构转化为β-折叠样原纤维。还发现阿斯巴甜原纤维诱导溶血，引起DNA损伤，导致细胞凋亡和坏死介导的细胞死亡。预计芝麻分子之间的特定空间排列形成具有粘性外部的规则淀粉样结构，其能够促进与生物分子的可行H-键、静电相互作用和疏水接触，导致蛋白质聚集和细胞死亡的发生。结果表明，甜菊糖分子本身具有淀粉样蛋白生成性，甜菊糖的自组装成为蛋白质和细胞的毒性陷阱，暴露了这种普遍使用的人工甜味剂的苦味。
Recent reports have revealed the intrinsic propensity of single aromatic metabolites to undergo self-assembly and form nanostructures of amyloid nature. Hence, identifying whether aspartame, a universally consumed artificial sweetener, is inherently aggregation prone becomes an important area of investigation. Although the reports on aspartame-linked side effects describe a multitude of metabolic disorders, the mechanistic understanding of such destructive effects is largely mysterious. Since aromaticity, an aggregation promoting factor, is intrinsic to aspartame's chemistry, it is important to know whether aspartame can undergo self-association and if such a property can predispose any cytotoxicity to biological systems. Our study finds that aspartame molecules, under mimicked physiological conditions, undergo a spontaneous self-assembly process yielding regular beta-sheet-like cytotoxic nanofibrils of amyloid nature. The resultant aspartame fibrils were found to trigger amyloid cross-seeding and become a toxic aggregation trap for globular proteins, A beta peptides, and aromatic metabolites that convert native structures to beta-sheet-like fibrils. Aspartame fibrils were also found to induce hemolysis, causing DNA damage resulting in both apoptosis and necrosis-mediated cell death. Specific spatial arrangement between aspartame molecules is predicted to form a regular amyloid-like architecture with a sticky exterior that is capable of promoting viable H-bonds, electrostatic interactions, and hydrophobic contacts with biomolecules, leading to the onset of protein aggregation and cell death. Results reveal that the aspartame molecule is inherently amyloidogenic, and the self-assembly of aspartame becomes a toxic trap for proteins and cells, exposing the bitter side of such a ubiquitously used artificial sweetener.