Please use this identifier to cite or link to this item:http://hdl.handle.net/20.500.12105/20128
Title
Ortho-methylated 3-hydroxypyridines hinder hen egg-white lysozyme fibrillogenesis
Author(s)
Date issued
2015-07-14
Citation
Mariño Perez L, Pauwels K, Casanovas R, Sanchis P, Vilanova Canet B, Muñoz Izquierdo F, et al. Ortho-methylated 3-hydroxypyridines hinder hen egg-white lysozyme fibrillogenesis. Sci Rep. 2015 Jul 14;5:12052.
Language
Inglés
Document type
research article
Abstract
Protein aggregation with the concomitant formation of amyloid fibrils is related to several neurodegenerative diseases, but also to non-neuropathic amyloidogenic diseases and non-neurophatic systemic amyloidosis. Lysozyme is the protein involved in the latter, and it is widely used as a model system to study the mechanisms underlying fibril formation and its inhibition. Several phenolic compounds have been reported as inhibitors of fibril formation. However, the anti-aggregating capacity of other heteroaromatic compounds has not been studied in any depth. We have screened the capacity of eleven different hydroxypyridines to affect the acid-induced fibrillization of hen lysozyme. Although most of the tested hydroxypyridines alter the fibrillation kinetics of HEWL, only 3-hydroxy-2-methylpyridine, 3-hydroxy-6-methylpyridine and 3-hydroxy-2,6- dimethylpyridine completely abolish fibril formation. Different biophysical techniques and several theoretical approaches are combined to elucidate their mechanism of action. O-methylated 3-hydroxypyridines bind non-cooperatively to two distinct but amyloidogenic regions of monomeric lysozyme. This stabilises the protein structure, as evidenced by enhanced thermal stability, and results in the inhibition of the conformational transition that precedes fibril assembly. Our results point to o-methylated 3-hydroxypyridines as a promising molecular scaffold for the future development of novel fibrillization inhibitors.
MESH
Protein Aggregation, Pathological | Binding Sites | Models, Molecular | Kinetics | Protein Aggregates | Hydrogen-Ion Concentration | Molecular Docking Simulation | Amyloid | Protein Stability | Muramidase | Thermodynamics | Pyridines | Animals | Microscopy, Atomic Force | Protein Binding | Protein Conformation | Proteolysis
DECS
Animales | Agregado de Proteínas | Microscopía de Fuerza Atómica | Muramidasa | Agregación Patológica de Proteínas | Simulación del Acoplamiento Molecular | Termodinámica | Concentración de Iones de Hidrógeno | Proteolisis | Piridinas | Amiloide | Modelos Moleculares | Sitios de Unión | Cinética | Conformación Proteica | Estabilidad Proteica | Unión Proteica
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