Glyceraldehyde-derived advanced glycation end-products having pyrrolopyridinium-based crosslinks

Abstract

Reducing sugars and reactive aldehydes, such as glyceraldehyde, non-enzymatically react with amino or guanidino groups of proteins to form advanced glycation end-products (AGEs) by the Maillard reaction that involves Schiff base formation followed by Amadori rearrangement. AGEs are found relatively in abundance in the human eye and to accumulate at a higher rate in diseases that impair vision such as cataract, diabetic retinopathy or age-related macular degeneration. We identified two novel AGEs of pyrrolopyridinium lysine dimer derived from glyceraldehyde, PPG1 and PPG2, in the Maillard reaction of N α -acetyl- l -lysine with glyceraldehyde under physiological conditions. Having fluorophores similar to that of vesperlysine A, which was isolated from the human lens, PPGs were found to act as photosensitizers producing singlet oxygen in response to blue light irradiation. Moreover, PPG2 interacts with receptor for AGE (RAGE) in vitro with a higher binding affinity than GLAP, a well-known ligand of the receptor. We also proposed a pathway to form PPGs and discussed how they would be formed in vitro . As glyceraldehyde-derived AGEs have been studied extensively in connection with various hyperglycemia-related diseases, further studies will be required to find PPGs in vivo such as in the lens or other tissues.

Structures of Toxic Advanced Glycation End-Products Derived from Glyceraldehyde, A Sugar Metabolite

“…To date, the following GA-AGE structures have been detected: triosidines [41], GLAP [42], PPGs [43], MG-H1 [44], and ArgP [45] (Figures 1 and 2). Trihydroxy-triosidine, GLAP, and PPGs were identified in the Lys residues and MG-H1 and ArgP in the Arg residues of proteins.…”

“…The pyridinium-type AGEs trihydroxy-triosidine and GLAP have been identified as GA-AGEs; however, their pathological effects are yet to be clarified. The Maillard reaction between N α -acetyl-L-Lys and GA was recently examined under physiological conditions and the main products identified were PPG1 and PPG2, which are fluorescent AGEs in which pyrrolopyridine ring structures cross-link two Lys molecules [43]. Based on these findings, a mechanism was proposed for the generation of PPG1 and PPG2 in vitro via a unique reaction to expand the skeleton as an alternative to the typical route for the formation of Schiff bases.…”

“…However, this protective effect was not observed when antibodies targeting other types of AGEs were used. Therefore, AGE structures containing epitopes recognized by the anti-GA-AGE antibody solely appear to be toxic, are called toxic AGEs (TAGE), and are distinct from other GA-AGEs, including triosidines [41], GA-derived pyridinium compounds (GLAP) [42], pyrrolopyridinium Lys dimers derived from GA (PPGs) [43], methylglyoxal (MGO)-derived hydroimidazolone 1 (MG-H1) [44], and argpyrimidine (ArgP) [45].…”

Is the Novel Slot Blot a Useful Method for Quantification of Intracellular Advanced Glycation End-Products?

“…However, this study revealed that argpyrimidine and MG-H1 were generated from glyceraldehyde in PANC-1 and HPDE cells. Finally, other structures of GA-AGEs (unidentified in the cell) [1,110,111] could be included in the modification data, identified, and quantified.…”