Non‐enzymatic glycation and glycoxidation protein products in foods and diseases: An interconnected, complex scenario fully open to innovative proteomic studies

Abstract

The Maillard reaction includes a complex network of processes affecting food and biopharmaceutical products; it also occurs in living organisms and has been strictly related to cell aging, to the pathogenesis of several (chronic) diseases, such as diabetes, uremia, cataract, liver cirrhosis and various neurodegenerative pathologies, as well as to peritoneal dialysis treatment. Dozens of compounds are involved in this process, among which a number of protein-adducted derivatives that have been simplistically defined as early, intermediate and advanced glycation end-products. In the last decade, various bottom-up proteomic approaches have been successfully used for the identification of glycation/glycoxidation protein targets as well as for the characterization of the corresponding adducts, including assignment of the modified amino acids. This article provides an updated overview of the mass spectrometry-based procedures developed to this purpose, emphasizing their partial limits with respect to current proteomic approaches for the analysis of other post-translational modifications. These limitations are mainly related to the concomitant sheer diversity, chemical complexity, and variable abundance of the various derivatives to be characterized. Some challenges to scientists are finally proposed for future proteomic investigations to solve main drawbacks in this research field.

Proteomic characterization of intermediate and advanced glycation end-products in commercial milk samples

“…glyoxal (G), methylglyoxal (MG), 3-deoxyglucosone (3-DG), 3-deoxygalactosone (3-DGal), 3-deoxypentosone (3-DPen) ( Supplementary Fig. S1) [6][7][8][9]. When model peptides/proteins were treated with these dicarbonyl compounds, the formation of the AGEs mentioned above and of: i) G-, MG-, 3-DG-and 3-DGal-derived hemiaminals (G-He, MG-He, 3-DG-He, and 3-DGal-He), ii) G-, MG-, 3-DG-and 3-DGal-derived dihydroxyimidazolines (G-DH, MG-DH, 3-DG-DH, and 3-DGal-DH), iii) G-, MG-, 3-DG-, and 3-DGal-derived hydroimidazolones (G-H, MG-H, 3-DG-H, and 3-DGal-H), iv) di-and tetra-hydropyrimidines (DHP and THP) was ascertained ( Supplementary Fig.…”

“…When model peptides/proteins were treated with these dicarbonyl compounds, the formation of the AGEs mentioned above and of: i) G-, MG-, 3-DG-and 3-DGal-derived hemiaminals (G-He, MG-He, 3-DG-He, and 3-DGal-He), ii) G-, MG-, 3-DG-and 3-DGal-derived dihydroxyimidazolines (G-DH, MG-DH, 3-DG-DH, and 3-DGal-DH), iii) G-, MG-, 3-DG-, and 3-DGal-derived hydroimidazolones (G-H, MG-H, 3-DG-H, and 3-DGal-H), iv) di-and tetra-hydropyrimidines (DHP and THP) was ascertained ( Supplementary Fig. S2) [9,10]. Lipid peroxidation products, by generating intermediate dicarbonyl compounds, can also contribute to the production of specific AGEs, such as CML [9,11,12].…”

Development of Diagnostic Fragment Ion Library for Glycated Peptides of Human Serum Albumin: Targeted Quantification in Prediabetic, Diabetic, and Microalbuminuria Plasma by Parallel Reaction Monitoring, SWATH, and MSE

“…Among these approaches, MS offers precise characterization of protein glycation, including the amino acid involved in the modification. Most of the AGEs reported in vitro and in vivo were discovered by MS-based techniques (18). AML modification has been extensively studied by different MS approaches.…”

“…Further specific neutral loss ions of 162 Da, 120 Da, and 84 Da and water loss of 36 Da arising from hexose moiety of glycated peptide were also considered as signature ions to validate the glycation of peptides in HSA (21,22). Similar characteristic patterns of water loss (18,36, and 54 Da) ions and immonium ions derived from lysine arising from AML-modified peptide were also used to identify glycated peptides (23,24). Diagnostic ions serve as the most reliable way of identifying glycated peptide by tandem mass spectrometry.…”

“…In this regard, a stable-isotope-dilution tandem mass spectrometry method was employed for simultaneous analysis of CML and CEL in hydrolysates of plasma proteins (28), and 13 C6-glucose was utilized to quantify glycated proteins in the plasma and erythrocytes (29,30). In a recent study, the glycationsensitive peptides of HSA that could serve as markers for early diagnosis of type 2 diabetes were quantified by using an MS-based 18 O-labeling technique (31). However, most of the previous studies have focused on AML modification, rather than other AGE modification.…”