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The melibiose-derived glycation product mimics a unique epitope present in human and animal tissues.

ABSTRACT: Non-enzymatic modification of proteins by carbohydrates, known as glycation, leads to generation of advanced glycation end-products (AGEs). In our study we used in vitro generated AGEs to model glycation in vivo. We discovered in vivo analogs of unusual melibiose-adducts designated MAGEs (mel-derived AGEs) synthesized in vitro under anhydrous conditions with bovine serum albumin and myoglobin. Using nuclear magnetic resonance spectroscopy we have identified MAGEs as a set of isomers, with open-chain and cyclic structures, of the fructosamine moiety. We generated a mouse anti-MAGE monoclonal antibody and show for the first time that the native and previously undescribed analogous glycation product exists in living organisms and is naturally present in tissues of both invertebrates and vertebrates, including humans. We also report MAGE cross-reactive auto-antibodies in patients with diabetes. We anticipate our approach for modeling glycation in vivo will be a foundational methodology in cell biology. Further studies relevant to the discovery of MAGE may contribute to clarifying disease mechanisms and to the development of novel therapeutic options for diabetic complications, neuropathology, and cancer.

SUBMITTER: Staniszewska M

PROVIDER: S-EPMC7859244 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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The melibiose-derived glycation product mimics a unique epitope present in human and animal tissues.

Staniszewska Magdalena M Bronowicka-Szydełko Agnieszka A Gostomska-Pampuch Kinga K Szkudlarek Jerzy J Bartyś Arkadiusz A Bieg Tadeusz T Gamian Elżbieta E Kochman Agata A Picur Bolesław B Pietkiewicz Jadwiga J Kuropka Piotr P Szeja Wiesław W Wiśniewski Jerzy J Ziółkowski Piotr P Gamian Andrzej A

Scientific reports 20210203 1

Non-enzymatic modification of proteins by carbohydrates, known as glycation, leads to generation of advanced glycation end-products (AGEs). In our study we used in vitro generated AGEs to model glycation in vivo. We discovered in vivo analogs of unusual melibiose-adducts designated MAGEs (mel-derived AGEs) synthesized in vitro under anhydrous conditions with bovine serum albumin and myoglobin. Using nuclear magnetic resonance spectroscopy we have identified MAGEs as a set of isomers, with open-c ...[more]

PMID: 33536563

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Project description:The strong links between (Human Leukocyte Antigen) HLA, infection and autoimmunity combine to implicate T-cells as primary triggers of autoimmune disease (AD). T-cell crossreactivity between microbially-derived peptides and self-peptides has been shown to break tolerance and trigger AD in experimental animal models. Detailed examination of the potential for T-cell crossreactivity to trigger human AD will require means of predicting which peptides might be recognised by autoimmune T-cell receptors (TCRs). Recent developments in high throughput sequencing and bioinformatics mean that it is now possible to link individual TCRs to specific pathologies for the first time. Deconvolution of TCR function requires knowledge of TCR specificity. Positional Scanning Combinatorial Peptide Libraries (PS-CPLs) can be used to predict HLA-restriction and define antigenic peptides derived from self and pathogen proteins. In silico search of the known terrestrial proteome with a prediction algorithm that ranks potential antigens in order of recognition likelihood requires complex, large-scale computations over several days that are infeasible on a personal computer. We decreased the time required for peptide searching to under 30 min using multiple blocks on graphics processing units (GPUs). This time-efficient, cost-effective hardware accelerator was used to screen bacterial and fungal human pathogens for peptide sequences predicted to activate a T-cell clone, InsB4, that was isolated from a patient with type 1 diabetes and recognised the insulin B-derived epitope HLVEALYLV in the context of disease-risk allele HLA A*0201. InsB4 was shown to kill HLA A*0201+ human insulin producing β-cells demonstrating that T-cells with this specificity might contribute to disease. The GPU-accelerated algorithm and multispecies pathogen proteomic databases were validated to discover pathogen-derived peptide sequences that acted as super-agonists for the InsB4 T-cell clone. Peptide-MHC tetramer binding and surface plasmon resonance were used to confirm that the InsB4 TCR bound to the highest-ranked peptide agonists derived from infectious bacteria and fungi. Adoption of GPU-accelerated prediction of T-cell agonists has the capacity to revolutionise our understanding of AD by identifying potential targets for autoimmune T-cells. This approach has further potential for dissecting T-cell responses to infectious disease and cancer.

Project description:BackgroundAdvanced glycation end products (AGEs) promote adverse health effects and may contribute to the multi-system functional decline observed in aging. Diet is a major source of AGEs, and foods high in protein may increase circulating AGE concentrations. However, epidemiological evidence that high-protein diets increase AGEs is lacking.ObjectivesWe examined whether dietary protein intake was associated with serum concentrations of the major AGE carboxymethyl-lysine (CML) and the soluble receptor for AGEs (sRAGE) in 2439 participants from the Health, Aging, and Body Composition study (mean age, 73.6 ± 2.9 y; 52% female; 37% black).MethodsCML and sRAGE were measured by ELISA, and the CML/sRAGE ratio was calculated. Protein intake was estimated using an interviewer-administered FFQ and categorized based on current recommendations for older adults: <0.8 g/kg/d (n = 1077), 0.8 to <1.2 g/kg/d (n = 922), and ≥1.2 g/kg/d (n = 440). Associations between protein intake and AGE-RAGE biomarkers were examined using linear regression models adjusted for demographics, height, lifestyle behaviors, prevalent disease, cognitive function, inflammation, and other dietary factors.ResultsCML concentrations were higher in individuals with higher total protein intake (adjusted least squares mean ± SE: <0.8 g/kg/d, 829 ± 17 ng/ml; 0.8 to <1.2 g/kg/d, 860 ± 15 ng/ml; ≥1.2 g/kg/d, 919 ± 23 ng/ml; P for trend = 0.001), as were sRAGE concentrations (<0.8 g/kg/d, 1412 ± 34 pg/ml; 0.8 to <1.2 g/kg/d, 1479 ± 31 pg/ml; ≥1.2 g/kg/d, 1574 ± 47 pg/ml; P for trend < 0.0001). Every 0.1 g/kg/d increment in total protein intake was associated with a 13.3 ± 3.0 ng/ml increment in CML and a 22.1 ± 6.0 pg/ml increment in sRAGE (P < 0.0001 for both). Higher CML and sRAGE concentrations were also associated with higher intakes of both animal and vegetable protein (all P values ≤ 0.01). There were no significant associations with the CML/sRAGE ratio.ConclusionsHigher dietary protein intake was associated with higher CML and sRAGE concentrations in older adults; however, the CML/sRAGE ratio remained similar across groups.

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The melibiose-derived glycation product mimics a unique epitope present in human and animal tissues.

Publications

The melibiose-derived glycation product mimics a unique epitope present in human and animal tissues.

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