**Abstract**

Protein glycation is the random, nonenzymatic reaction of sugar and protein induced by diabetes and ageing; this process is quite different from glycosylation mediated by the enzymatic reactions catalysed by glycosyltransferases. Schiff bases form advanced glycation end products (AGEs) via intermediates, such as Amadori compounds. Although these AGEs form various molecular species, only a few of their structures have been determined. AGEs bind to different AGE receptors on the cell membrane and transmit signals to the cell. Signal transduction via the receptor of AGEs produces reactive oxygen species in cells, and oxidative stress is responsible for the onset of diabetic complications. This chapter introduces the molecular mechanisms of disease onset due to oxidative stress, including reactive oxygen species, caused by AGEs generated by protein glycation in a hyperglycaemic environment.

**Keywords:** glycation, advanced glycation end products, gestational diabetes, reactive oxygen species, oxidative stress

## **1. Introduction**

Glycosylation is a post-translational modification mediated by an enzymatic reaction catalysed by glycosyltransferases, which add a carbohydrate molecule to a predetermined region of a protein. More than 300 glycosyltransferases have been identified in mammals [1]. In contrast, glycation is a random nonenzymatic reaction that occurs under conditions of hyperglycaemia and ageing. The reactive reducing ends of free sugars (e.g., glucose, fructose, and galactose) covalently attach to the amino acid residue of the protein, thereby creating glycated products.

Glycation has been previously studied. Robert Lynn from the United Kingdom first reported that proteins and reducing sugars react during the beer-making process to form new compounds [2]. Subsequently, the French chemist Louis-Camille Maillard discovered that heating a mixed solution of amino acids and reducing sugars produced a brown compound [3]; this was the first report of the Maillard reaction or aminocarbonyl reaction, which is a nonenzymatic reaction between the amino group of an amino acid and carbonyl group of a reducing sugar (**Figure 1**).

In the early stages of the Maillard reaction, the imine produced by the nucleophilic reaction of the amino group and carboxyl group becomes a stable Amadori compound through Amadori rearrangement. The Amadori compound then undergoes a repeated polycondensation reaction with an amino compound using ozone or

#### **Figure 1.**

*Maillard reaction in foods and the formation of AGEs. (A) Proteins contained in foods are saccharified during fermentation and processing, and the Maillard reaction is accompanied by browning/denaturation. (B) The amino group of the amino acid of the protein and the carbonyl group of the reducing sugar react nonenzymatically, and AGEs are produced by repeating oxidation, dehydration, and condensation from the Schiff base via the Amadori compound.*

furfural as an intermediate to produce a brown product, melainodin, in late stages [4]. Structures formed in the latter stage of the nonenzymatic glycation reaction between reducing sugars and proteins are collectively known as advanced glycation end products (AGEs).

Fermented foods, such as dark beer, miso, and soy sauce, contain large amounts of AGEs, including 3-deoxyglucosone and melanoidin [5]. Additionally, milk, cheese, and butter contain carboxymethyl lysine (CML) [6]. These chemicals are consumed on a daily basis and some AGEs, such as carbonyl compounds and CML, which are closely related to disease states, are known to be glycotoxins. Many studies have evaluated the adverse health effects of ingesting glycotoxins present in such foods in relation to nephropathy [7–9], type 2 diabetes [10, 11], and arteriosclerosis [12]; however, these relationships are not completely understood. Therefore, research on phytochemicals that prevent adverse effects on the living body caused by ingestion of these glycotoxins is being conducted [13–15].

In this chapter, we first introduce the biochemical properties of AGEs and their reaction processes. We then discuss intracellular signal transduction systems related to oxidative stress caused by AGEs in a hyperglycaemic environment and describe the relationships between AGEs and diseases.
