Phenylalanine Oligomers and Fibrils: The Mechanism of Assembly and the Importance of Tetramers and Counterions
Phenylalanine Oligomers and Fibrils: The Mechanism of Assembly and the Importance of Tetramers and Counterions
复制标题
DOI：
10.1021/jacs.5b05482
复制
发表时间：
2015-08-19
影响因子：
15
通讯作者：
Bowers, Michael T.
中科院分区：
文献类型：
--
作者：
Do, Thanh D.;Kincannon, William M.;Bowers, Michael T.
苯丙氨酸是已知的唯一一种自组装成有毒纤维聚集体的氨基酸。血液中苯丙氨酸浓度升高会导致苯丙酮尿症，这是一种进行性精神发育迟缓。用离子迁移率质谱仪研究了聚集级联早期形成的苯丙氨酸低聚物的结构和分布。实验截面表明，苯丙氨酸在中性pH条件下自组装成由四个单体组成的多层低聚物。单体排列形成一个由两性离子末端组成的亲水核心，并将疏水的芳香族侧链暴露在外面。在高pH条件下，中性氨基和带负电荷的苯丙氨酸羧酸盐之间的相互作用允许形成少量梯形低聚物，并在离子迁移率实验中被检测到。然而，像铵这样的反离子将这些结构重新排列成在中性pH下观察到的相同结构。Phe低聚体和纤维的细胞毒性可能是由于疏水的表面与细胞膜之间的良好相互作用以及Phe低聚体的亲水核心与离子之间的强相互作用而导致的离子泄漏和细胞损伤。
Phenylalanine is the only amino acid known to self-assemble into toxic fibrillar aggregates. An elevated concentration of phenylalanine in the blood can result in Phenylketonuria, a progressive mental retardation. Ion-mobility mass spectrometry is employed to investigate the structure and distribution of phenylalanine oligomers formed in the early stage of the aggregation cascade. The experimental cross sections indicate that phenyl-alanine self-assembles at neutral pH into oligomers composed of multiple layers of four monomers. The monomers arrange themselves to create a hydrophilic core made of zwitterionic termini and expose hydrophobic aromatic side chains to the outside. At high pH, the interactions between the neutral amino and negatively charged carboxylate of phenylalanine allow a minor population of ladder-like oligomers to be formed and detected in ion-mobility experiments. However, counterions such as ammonium rearrange those structures into the same structures observed at neutral pH. The cytotoxicity of Phe oligomers and fibrils may be due to favorable interactions between the hydrophobic exterior and the cell membrane and strong interactions between the hydrophilic core of Phe oligomers and ions, resulting in ion leakage and cellular damage.