Chiral Interface of Amyloid Beta (Aβ): Relevance to Protein Aging, Aggregation and Neurodegeneration

Autor: Victor V. Dyakin, Thomas Wisniewski, Abel Lajtha
Jazyk: angličtina
Rok vydání: 2020
Předmět:
Zdroj: Symmetry
Volume 12
Issue 4
Symmetry, Vol 12, Iss 585, p 585 (2020)
ISSN: 2073-8994
DOI: 10.3390/sym12040585
Popis: 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 NE). PTMs NE 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 Enz and PTMs Sp) 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 (A&beta
) peptide, known for its essential cellular functions and associations with neuropathology. The widely discussed amyloid cascade hypothesis (ACH) of Alzheimer&rsquo
s disease (AD) states that disease pathogenesis is initiated by the oligomerization and subsequent aggregation of the A&beta
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 A&beta
drug-targeting therapies requires the reconsolidation of the ACH with the concept of PTMs Sp. 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 A&beta
Extensive recent experimental results describe the truncated, isomerized and racemized forms of A&beta
and the interplay between enzymatic and PTMs Sp. Currently, accumulated data suggest that non-enzymatic PTMs Sp 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 Sp impact the functions of many proteins and peptides, including A&beta
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 Sp and RHPA
Databáze: OpenAIRE
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