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  • Title: Oxidative modifications in glycated insulin.
    Author: Guedes S, Vitorino R, Domingues MR, Amado F, Domingues P.
    Journal: Anal Bioanal Chem; 2010 Jul; 397(5):1985-95. PubMed ID: 20496032.
    Abstract:
    At the present, the term "glycoxidation" is recognized as the synergistic interaction between glycation and oxidative processes which, with the help of redox-active metals, consequently leads to the production of deleterious tissue modifications. The association between glycation and oxidation events is considered one of the major factors in the accumulation of non-functional damaged proteins, enhancing the oxidative damage at the cellular level. Because of the central role of insulin in the biology of diabetes, we investigated the site-specific oxidation of native and glycated insulin (mono, di, and tri-glycated forms), through metal-catalyzed oxidation, with a combination of liquid chromatography and mass spectrometry. With this approach we were able to identify the residues that were mainly oxidized, and peptide sequences resulting from oxidative cleavage of insulin. Tyrosine, phenylalanine, and cysteine were the main affected residues. Time-course analysis (0-48 h) of the oxidative damage enabled to detect more pronounced and earlier oxidative modifications in the case of glycated insulin. We also observed more severe oxidative damage as the number of glycation sites increased in insulin. These oxidative modifications included other oxidized residues, namely proline, histidine, valine, leucine, and glycine, which were shown to be carbonylated. In addition, we identified new sites of peptide cleavage with the formation of new fragments, derived mainly from chain B, which were both glycated and oxidatively modified. Peptide fragmentation occurred mainly between the residues phenylalanine, glycine, leucine, and tyrosine. Moreover, for diglycated and triglycated forms we observed further oxidative cleavage occurring in both chains, with oxidation and fragmentation of residues occurring near cysteine bridges, especially in chain A.
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