Dyakin Victor V, Wisniewski Thomas M, Lajtha Abel
Departmemts: Virtual Reality Perception Lab. (VV. Dyakin) and Center for Neurochemistry (A. Lajtha), The Nathan S. Kline Institute for Psychiatric Research (NKI), Orangeburg, NY 10962, USA.
Departments of Neurology, Pathology and Psychiatry, Center for Cognitive Neurology, New York University School of Medicine, New York, NY 10016, USA.
Symmetry (Basel). 2020 Apr;12(4). doi: 10.3390/sym12040585. Epub 2020 Apr 7.
Biochirality is the subject of distinct branches of science, including biophysics, biochemistry, the stereochemistry of protein folding, neuroscience, brain functional laterality and bioinformatics. At the protein level, biochirality is closely associated with various post-translational modifications (PTMs) accompanied by the non-equilibrium phase transitions (PhTs ). PTMs support the dynamic balance of the prevalent chirality of enzymes and their substrates. The stereoselective nature of most biochemical reactions is evident in the enzymatic (Enz) and spontaneous (Sp) PTMs (PTMs and PTMs ) of proteins. Protein chirality, which embraces biophysics and biochemistry, is a subject of this review. In this broad field, we focus attention to the amyloid-beta (Aβ) peptide, known for its essential cellular functions and associations with neuropathology. The widely discussed amyloid cascade hypothesis (ACH) of Alzheimer's disease (AD) states that disease pathogenesis is initiated by the oligomerization and subsequent aggregation of the Aβ peptide into plaques. The racemization-induced aggregation of protein and RNA have been extensively studied in the search for the contribution of spontaneous stochastic stereo-specific mechanisms that are common for both kinds of biomolecules. The failure of numerous Aβ drug-targeting therapies requires the reconsolidation of the ACH with the concept of PTMs . The progress in methods of chiral discrimination can help overcome previous limitations in the understanding of AD pathogenesis. The primary target of attention becomes the network of stereospecific PTMs that affect the aggregation of many pathogenic agents, including Aβ. Extensive recent experimental results describe the truncated, isomerized and racemized forms of Aβ and the interplay between enzymatic and PTMs . Currently, accumulated data suggest that non-enzymatic PTMs occur in parallel to an existing metabolic network of enzymatic pathways, meaning that the presence and activity of enzymes does not prevent non-enzymatic reactions from occurring. PTMs impact the functions of many proteins and peptides, including Aβ. This is in logical agreement with the silently accepted racemization hypothesis of protein aggregation (RHPA). Therefore, the ACH of AD should be complemented by the concept of PTMs and RHPA.
生物手性是多个不同科学分支的研究主题，包括生物物理学、生物化学、蛋白质折叠的立体化学、神经科学、大脑功能偏侧性和生物信息学。在蛋白质水平上，生物手性与各种翻译后修饰（PTM）密切相关，这些修饰伴随着非平衡相变（PhT）。PTM维持着酶及其底物普遍手性的动态平衡。大多数生化反应的立体选择性在蛋白质的酶促（Enz）和自发（Sp）PTM（PTM 和PTM）中很明显。包含生物物理学和生物化学的蛋白质手性是本综述的主题。在这个广泛的领域中，我们将注意力集中在淀粉样β（Aβ）肽上，它以其重要的细胞功能以及与神经病理学的关联而闻名。广泛讨论的阿尔茨海默病（AD）淀粉样蛋白级联假说（ACH）指出，疾病发病机制始于Aβ肽的寡聚化以及随后聚集成斑块。在寻找蛋白质和RNA的外消旋化诱导聚集过程中，人们广泛研究了自发随机立体特异性机制对这两种生物分子的共同作用。众多针对Aβ的药物靶向治疗的失败要求将ACH与PTM的概念重新整合。手性识别方法的进展有助于克服以往在理解AD发病机制方面的局限性。主要关注目标变成了影响包括Aβ在内的许多病原体聚集的立体特异性PTM网络。最近大量的实验结果描述了Aβ的截短、异构化和外消旋化形式以及酶促PTM和PTM之间的相互作用。目前，积累的数据表明非酶促PTM与现有的酶促途径代谢网络并行发生，这意味着酶的存在和活性并不能阻止非酶促反应的发生。PTM影响许多蛋白质和肽的功能，包括Aβ。这与默默被接受的蛋白质聚集外消旋化假说（RHPA）在逻辑上是一致的。因此，AD的ACH应该用PTM和RHPA的概念来补充。
