Detection of AGEs as markers for carbohydrate metabolism and protein denaturation

Abstract

Approximately 100 years have passed since the Maillard reaction was first reported in the field of food chemistry as a condensation reaction between reducing sugars and amino acids. This reaction is thought to progress slowly primarily from glucose with proteins in vivo. An early-stage product, called the "Amadori product", is converted into advanced glycation end products. Those accumulate in the body in accordance with age, with such accumulation being enhanced by lifestyle-related diseases that result in the denaturation of proteins. Recent studies have demonstrated that intermediate carbonyls are generated by several pathways, and rapidly generate many glycation products. However, accurate quantification of glycation products in vivo is difficult due to instability and differences in physicochemical properties. In this connection, little is known about the relationship between the structure of glycation products and pathology. Furthermore, the interaction between proteins modified by glycation and receptors for advanced glycation end products is also known to induce the production of several inflammatory cytokines. Therefore, those inhibitors have been developed over the world to prevent lifestyle-related diseases. In this review, we describe the process of protein denaturation induced by glycation and discuss the possibility of using the process as a marker of age-related diseases.

Keywords: AGEs; aging; diabetic complications; glycation; post-translational modification.

Fig. 1

Maillard Reaction. Reducing sugars such as glucose and ribose react with amino residues of proteins and free amino acid, and reaction that occurs between reducing sugars and generate AGEs through formation of Schiff base and Amadori products. AGEs are characterized by a yellow-brown color, an autofluorescence, intra- and intermolecular cross-linkings. AGEs are recognized by several AGEs receptor such as receptor for AGE (RAGE), and AGEs-RAGE interaction is reported to activate cell signaling pathways. AGEs accumulate in the body in accordance with age, with such accumulation being enhanced by lifestyle-related diseases such as diabetic complications that result in the denaturation of proteins.

Fig. 2

Possible pathway for AGEs formation and those biological impacts to protein modification. The Maillard reaction proceeds in vivo between reducing sugars and proteins, resulting in the induction of denaturation of proteins. Intermediate aldehydes such as glyoxal, methylglyoxal, glucosone and glycolaldehyde rapidly modify proteins in vivo.

Fig. 3

Reported AGEs structures. AGEs are generated not only from glucose but also from intermediate carbonyls via glycolysis, lipid peroxidation and inflammatory response. Typical AGEs structures were shown among AGE structures reported to date.

Fig. 4

Usefulness of antibody library against AGEs structures. Monoclonal anti-AGEs antibodies that epitope structures were identified are useful for evaluating the biological significance of AGEs such as localization, pathway for AGE formation and screening of AGE inhibitors.

Fig. 5

Succination of adiponectin proteins by fumarate affects the secretion and condensation in adipocytes. 2SC is formed by a reaction between the thiol group of proteins and fumarate, a Krebs cycle intermediate. 2SC-proteins such as adiponectin increased in adipocytes under hyperglycemic condition, resulting in the hyposecretion and malcondensation of adiponectin.