Glycation of H1 Histone by 3-Deoxyglucosone: Effects on Protein Structure and Generation of Different Advanced Glycation End Products

Jalaluddin Mohammad Ashraf,Inho Choi,Saheem Ahmad,Gulam Rabbani,Rizwan Hasan Khan,Qambar Hasan,Khursheed Alam,Vladimir N Uversky

doi:10.1371/journal.pone.0130630

Abstract

Advanced glycation end products (AGEs) culminate from the non-enzymatic reaction between a free carbonyl group of a reducing sugar and free amino group of proteins. 3-deoxyglucosone (3-DG) is one of the dicarbonyl species that rapidly forms several protein-AGE complexes that are believed to be involved in the pathogenesis of several diseases, particularly diabetic complications. In this study, the generation of AGEs (Nε-carboxymethyl lysine and pentosidine) by 3-DG in H1 histone protein was characterized by evaluating extent of side chain modification (lysine and arginine) and formation of Amadori products as well as carbonyl contents using several physicochemical techniques. Results strongly suggested that 3-DG is a potent glycating agent that forms various intermediates and AGEs during glycation reactions and affects the secondary structure of the H1 protein. Structural changes and AGE formation may influence the function of H1 histone and compromise chromatin structures in cases of secondary diabetic complications.

Highlights

Advanced glycation end products (AGEs) are a heterogeneous group of complex molecules that include reactive derivatives generated during the non-enzymatic glycation process in which reducing sugars react with the free amino groups of amino acids, proteins, lipoproteins, and nucleic acids
High levels of AGEs in the body are associated with a large number of diseases including secondary complications of diabetes, renal failure, and Alzheimer’s disease [49, 50]. 3-DG concentration has been reported to be higher in diabetic subjects, and AGEs play a major role in the initiation and/or progression of diabetic complications [51, 52]
The presence of Amadori products and carbonyl contents in 3-DG-modified H1 histone confirms the occurrence of glycation reaction

Summary

Introduction

Advanced glycation end products (AGEs) are a heterogeneous group of complex molecules that include reactive derivatives generated during the non-enzymatic glycation process in which reducing sugars react with the free amino groups of amino acids, proteins, lipoproteins, and nucleic acids. Indigenous α-dicarbonyl intermediates are formed through various mechanisms and pathways such as the glycolytic pathway, auto-oxidation of glucose, during all stages of Maillard reaction, and lipid peroxidation [10,11,12,13]. These entities are very reactive (20,000 times that of reducing sugars), and react swiftly with arginine and lysine residues on proteins; AGEs can be formed even with extremely low concentrations of α-dicarbonyls [14, 15]. Among the α-dicarbonyls, 3-deoxyglucosone (3-DG), methylglyoxal (MG), and glyoxal are the major precursors of AGEs [16, 17]. 3-DG levels are elevated in patients with diabetes [18], and its role in the development of secondary diabetic complications has been reported [19]

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Results

Conclusion