Glycation of Lys-16 and Arg-5 in amyloid-β and the presence of Cu2+ play a major role in the oxidative stress mechanism of Alzheimer’s disease
| Autor: | Nathaniel D Durfee, Nathaniel J. Henning, Sydney O. Shuster, Staci A. Hill, David R Stillman, Gregory Joon Kee Bowe, Sunhee Choi, Sebastian M. Fica-Contreras, Geoffrey D Vrla, Roger K. Sandwick, Kelly M Suralik |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
chemistry.chemical_classification biology Amyloid beta Superoxide Methylglyoxal Peptide 010402 general chemistry medicine.disease_cause 01 natural sciences Biochemistry 0104 chemical sciences Inorganic Chemistry 03 medical and health sciences chemistry.chemical_compound 030104 developmental biology chemistry Glycation biology.protein medicine Hydroxyl radical Oxidative stress Histidine |
| Zdroj: | JBIC Journal of Biological Inorganic Chemistry. 22:1211-1222 |
| ISSN: | 1432-1327 0949-8257 |
| Popis: | Extensive research has linked the amyloid-beta (Aβ) peptide to neurological dysfunction in Alzheimer's disease (AD). Insoluble Aβ plaques in the AD patient brain contain high concentrations of advanced glycation end-products (AGEs) as well as transition metal ions. This research elucidated the roles of Aβ, sugars, and Cu2+ in the oxidative stress mechanism of AD at the molecular level. Mass spectral (MS) analysis of the reactions of Aβ with two representative sugars, ribose-5-phosphate (R5P) and methylglyoxal (MG), revealed Lys-16 and Arg-5 as the primary glycation sites. Quantitative analysis of superoxide [Formula: see text] production by a cyt c assay showed that Lys-16 generated four times as much [Formula: see text] as Arg-5. Lys-16 and Arg-5 in Aβ1-40 are both adjacent to histidine residues, which are suggested to catalyze glycation. Additionally, Lys-16 is close to the central hydrophobic core (Leu-17-Ala-21) and to His-13, both of which are known to lower the pKa of the residue, leading to increased deprotonation of the amine and an enhanced glycation reactivity compared to Arg-5. Gel electrophoresis results indicated that all three components of AD plaques-Aβ1-40, sugars, and Cu2+-are necessary for DNA damage. It is concluded that the glycation of Aβ1-40 with sugars generates significant amounts of [Formula: see text], owing to the rapid glycation of Lys-16 and Arg-5. In the presence of Cu2+, [Formula: see text] converts to hydroxyl radical (HO·), the source of oxidative stress in AD. |
| Databáze: | OpenAIRE |
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