Department of Bioscience and Bioengineering, Indian Institute of Technology Jodhpur, Jodhpur, India, 340012.
School of Life Sciences, Jawaharlal Nehru University, New Delhi, 110067, India.
Sci Rep. 2017 Sep 11;7(1):11146. doi: 10.1038/s41598-017-10911-z.
Excess accumulation of phenylalanine is the characteristic of untreated Phenylketonuria (PKU), a well-known genetic abnormality, which triggers several neurological, physical and developmental severities. However, the fundamental mechanism behind the origin of such diverse health problems, particularly the issue of how they are related to the build-up of phenylalanine molecules in the body, is largely unknown. Here, we show cross-seeding ability of phenylalanine fibrils that can effectively initiate an aggregation process in proteins under physiological conditions, converting native protein structures to β-sheet assembly. The resultant fibrils were found to cause severe hemolysis, yielding a plethora of deformed erythrocytes that is highly relevant to phenylketonuria. Unique arrangement of zwitterionic phenylalanine molecules in their amyloid-like higher order entities is predicted to promote both hydrophobic and electrostatic interaction, sufficient enough to trap proteins and to preferentially interact with the membrane components of RBCs. Since the prevalence of hemolysis and amyloid related psychoneurological severities are mostly observed in PKU patients, we propose that the inherent property of phenylalanine fibrils to trigger hemolysis and to induce protein aggregation may have direct relevance to the disease mechanism of PKU.
苯丙氨酸的过度积累是未经治疗的苯丙酮尿症（PKU）的特征，PKU 是一种已知的遗传异常，可引发多种神经、身体和发育方面的严重问题。然而，这种多种健康问题的根本原因，特别是它们与体内苯丙氨酸分子积累的关系问题，在很大程度上仍不清楚。在这里，我们展示了苯丙氨酸原纤维的交叉成核能力，它可以在生理条件下有效地引发蛋白质的聚集过程，将天然蛋白质结构转化为β-折叠组装。结果发现原纤维会引起严重的溶血，产生大量变形的红细胞，这与苯丙酮尿症高度相关。预测其类似淀粉样的更高阶实体中两性离子苯丙氨酸分子的独特排列方式，可促进疏水性和静电相互作用，足以捕获蛋白质，并优先与 RBC 的膜成分相互作用。由于溶血和与淀粉样相关的神经精神严重程度的普遍性在 PKU 患者中大多观察到，我们提出苯丙氨酸原纤维引发溶血和诱导蛋白质聚集的固有特性可能与 PKU 的疾病机制直接相关。
