title: Glycation of Lysozyme by Glycolaldehyde Provides New Mechanistic Insights in Diabetes-Related Protein Aggregation.
abstract: Glycation occurs in vivo as a result of the nonenzymatic reaction of carbohydrates (and/or their autoxidation products) with proteins, DNA, or lipids. Protein glycation causes loss-of-function and, consequently, the development of diabetic-related diseases. Glycation also boosts protein aggregation, which can be directly related with the higher prevalence of aggregating diseases in diabetic people. However, the molecular mechanism connecting glycation with aggregation still remains unclear. Previously we described mechanistically how glycation of hen egg-white lysozyme (HEWL) with ribose induced its aggregation. Here we address the question of whether the ribose-induced aggregation is a general process or it depends on the chemical nature of the glycating agent. Glycation of HEWL with glycolaldehyde occurs through two different scenarios depending on the HEWL concentration regime (both within the micromolar range). At low HEWL concentration, non-cross-linking fluorescent advanced glycation end-products (AGEs) are formed on Lys side chains, which do not change the protein structure but inhibit its enzymatic activity. These AGEs have little impact on HEWL surface hydrophobicity and, therefore, a negligible effect on its aggregation propensity. Upon increasing HEWL concentration, the glycation mechanism shifts toward the formation of intermolecular cross-links, which triggers a polymerization cascade involving the formation of insoluble spherical-like aggregates. These results notably differ with the aggregation-modulation mechanism of ribosylated HEWL directed by hydrophobic interactions. Additionally, their comparison constitutes the first experimental evidence showing that the mechanism underlying the aggregation of a glycated protein depends on the chemical nature of the glycating agent.
authors.affiliation: University Institute of Health Sciences (UNICS-IdisPa) , Ctra. Valldemossa 79, E-07010, Palma de Mallorca, Spain.|Departament de Química, Universitat de les Illes Balears , Ctra. Valldemossa km 7.5, E-07122, Palma de Mallorca, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Mariño
authors.affiliation: Departament de Química, Universitat de les Illes Balears , Ctra. Valldemossa km 7.5, E-07122, Palma de Mallorca, Spain.
authors.forename: Carlos Andrés
authors.initials: CA
authors.lastname: Maya-Aguirre
authors.affiliation: Structural Biology Brussels, Vrije Universiteit Brussels , Pleinlaan 2, 1050 Brussels, Belgium.|VIB Structural Biology Research Centre, Vlaams Instituut voor Biotechnologie , Pleinlaan 2, 1050 Brussels, Belgium.
authors.forename: Kris
authors.initials: K
authors.lastname: Pauwels
authors.affiliation: University Institute of Health Sciences (UNICS-IdisPa) , Ctra. Valldemossa 79, E-07010, Palma de Mallorca, Spain.|Departament de Química, Universitat de les Illes Balears , Ctra. Valldemossa km 7.5, E-07122, Palma de Mallorca, Spain.
authors.forename: Bartolomé
authors.initials: B
authors.lastname: Vilanova
authors.affiliation: University Institute of Health Sciences (UNICS-IdisPa) , Ctra. Valldemossa 79, E-07010, Palma de Mallorca, Spain.|Departament de Química, Universitat de les Illes Balears , Ctra. Valldemossa km 7.5, E-07122, Palma de Mallorca, Spain.
authors.forename: Joaquin
authors.identifier: 0000-0001-8131-0315
authors.initials: J
authors.lastname: Ortega-Castro
authors.affiliation: University Institute of Health Sciences (UNICS-IdisPa) , Ctra. Valldemossa 79, E-07010, Palma de Mallorca, Spain.|Departament de Química, Universitat de les Illes Balears , Ctra. Valldemossa km 7.5, E-07122, Palma de Mallorca, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Frau
authors.affiliation: University Institute of Health Sciences (UNICS-IdisPa) , Ctra. Valldemossa 79, E-07010, Palma de Mallorca, Spain.|Departament de Química, Universitat de les Illes Balears , Ctra. Valldemossa km 7.5, E-07122, Palma de Mallorca, Spain.
authors.forename: Josefa
authors.initials: J
authors.lastname: Donoso
authors.affiliation: University Institute of Health Sciences (UNICS-IdisPa) , Ctra. Valldemossa 79, E-07010, Palma de Mallorca, Spain.|Departament de Química, Universitat de les Illes Balears , Ctra. Valldemossa km 7.5, E-07122, Palma de Mallorca, Spain.
authors.forename: Miquel
authors.identifier: 0000-0002-4211-9013
authors.initials: M
authors.lastname: Adrover
mesh_terms: D000079:Acetaldehyde / Q000031:analogs & derivatives* / Q000378:metabolism; D000818:Animals; D002645:Chickens; D003920:Diabetes Mellitus / Q000378:metabolism*; D017127:Glycation End Products, Advanced / Q000737:chemistry / Q000378:metabolism; D006031:Glycosylation; D057927:Hydrophobic and Hydrophilic Interactions; D009113:Muramidase / Q000378:metabolism*; D011487:Protein Conformation; D011506:Proteins / Q000378:metabolism*; D013050:Spectrometry, Fluorescence; D013499:Surface Properties
chemical_list: D017127:Glycation End Products, Advanced; D011506:Proteins; C421864:hen egg lysozyme; D009113:Muramidase; D000079:Acetaldehyde; C010972:glycolaldehyde