MEDICAL HYPOTHESES AND RESEARCH
VOL. 1, No. 2 / 3, July 2004
R. Nagai  Med Hypotheses Res 1: 161-170.
Accumulation of Advanced Glycation End Products in
Department of Medical Biochemistry, Kumamoto University Graduate School of Medical
and Pharmaceutical sciences, Honjo 1-1-1, Kumamoto 860-8556, Japan
Abstract. Incubation of proteins with reducing sugars such as glucose and fructose
lead, through formation of Schiff bases and Amadori products, to the generation of
advanced glycation end-products (AGE) of the Maillard reaction. Recent studies have
demonstrated that accumulation of AGE in tissue proteins increases with the pathogenesis of
diabetic complications and atherosclerosis, strongly suggests an association of AGE for the
development of age-related disorders. Since this reaction progresses non-enzymatically
almost all of the proteins in accordance with reducing sugar concentration and the half-life
of each protein, it is different from enzymatic post-translational modification such as
phosphorylation and acetylation of some specific proteins. Although the formation of
Amadori product, relatively stable intermediates of the reaction, is reversible, the formation
of AGE is irreversible reaction, indicating that AGE-formation may result in the irreversible
denature and inactivation of proteins in vivo. Although the formation of AGE was believed
to proceed on extracellular lesion from the relatively inert aldehyde such as glucose, many
recent publications have strongly demonstrated that AGE is also formed on intracellular
space from more reactive intermediates in carbohydrate metabolism. Furthermore, several
AGE inhibitors such as pyridoxamine and thiamine have shown promise in model systems
for inhibiting both the Maillard reaction and the development of diabetic complications.
This review describes the proposed pathways for the formation of AGE during the Maillard
reaction and role of the reaction in the pathogenesis of age-related diseases.
*Address all correspondence to: Dr. Ryoji Nagai, Department of Medical Biochemistry,
Kumamoto University Graduate School of Medical and Pharmaceutical sciences, Honjo
1-1-1, Kumamoto 860-8556, Japan. Phone: 81-96-373-5071. Fax: 81-96-364-6940.
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