A Post-Amadori Inhibitor Pyridoxamine Also Inhibits Chemical Modification of Proteins by Scavenging Carbonyl Intermediates of Carbohydrate and Lipid Degradation

Abstract

Reactive carbonyl compounds are formed during autoxidation of carbohydrates and peroxidation of lipids. These compounds are intermediates in the formation of advanced glycation end products (AGE) and advanced lipoxidation end products (ALE) in tissue proteins during aging and in chronic disease. We studied the reaction of carbonyl compounds glyoxal (GO) and glycolaldehyde (GLA) with pyridoxamine (PM), a potent postAmadori inhibitor of AGE formation in vitro and of development of renal and retinal pathology in diabetic animals. PM reacted rapidly with GO and GLA in neutral, aqueous buffer, forming a Schiff base intermediate that cyclized to a hemiaminal adduct by intramolecular reaction with the phenolic hydroxyl group of PM. This bicyclic intermediate dimerized to form a five-ring compound with a central piperazine ring, which was characterized by electrospray ionization-liquid chromatography/mass spectrometry, NMR, and x-ray crystallography. PM also inhibited the modification of lysine residues and loss of enzymatic activity of RNase in the presence of GO and GLA and inhibited formation of the AGE/ALE N ⑀ -(carboxymethyl)lysine during reaction of GO and GLA with bovine serum albumin. Our data suggest that the AGE/ALE inhibitory activity and the therapeutic effects of PM observed in diabetic animal models depend, at least in part, on its ability to trap reactive carbonyl intermediates in AGE/ALE formation, thereby inhibiting the chemical modification of tissue proteins.

Pyridorin in Type 2 Diabetic Nephropathy

“…The agent has been shown to interfere with the nonenzymatic modification of proteins by altering the ability of glucose to cause oxidative formation of advanced glycation end products via the Amadori pathway and oxidative modification of tryptophane residues mediated by reactive oxygen species. 5,8,9 Pyridorin has also been demonstrated to have the ability to trap reactive carboxyl intermediates that lead to the formation of advanced glycation end products and advanced lipoxidation end products, both of which have been implicated in the pathophysiology of diabetic renal and retinal lesions. 5,8,9,21,22 Pyridorin can trap malondialdehyde, an important intermediary in the formation of advanced lipoxidation end products during lipid peroxidation.…”

“…5,8,9 Pyridorin has also been demonstrated to have the ability to trap reactive carboxyl intermediates that lead to the formation of advanced glycation end products and advanced lipoxidation end products, both of which have been implicated in the pathophysiology of diabetic renal and retinal lesions. 5,8,9,21,22 Pyridorin can trap malondialdehyde, an important intermediary in the formation of advanced lipoxidation end products during lipid peroxidation. 23 Thus, on the basis of its biochemical activities, Pyridorin would appear to be a promising candidate.…”

“…Pyridorin is an efficient inhibitor of advanced glycation end products and glycoxidative reactions in various biologic systems. [4][5][6][7][8][9] Further, Pyridorin is a chemical scavenger of pathogenic reactive carbonyl species and has been shown to inhibit formation of advanced lipoxidation end products during lipid peroxidation reactions. 7,8 These biochemical characteristics suggest the possibility that Pyridorin may be a novel agent targeting several pathogenetic pathways that may be relevant to the progression of diabetic kidney disease.…”

Modification of Collagen IV by Glucose or Methylglyoxal Alters Distinct Mesangial Cell Functions

“…Plates were then washed to remove free reagents, and CML residues were determined by ELISA using polyclonal anti-AGE antibody R618, which recognizes protein-CML as an antigenic epitope. 28 Modification of collagen arginine residues to MG-H1 was determined using monoclonal antibody 1H7G5, (a gift from Dr. Michael Brownlee, Albert Einstein University, Bronx, NY 29 ).…”

Diabetic Glomerulopathy

“…It scavenges pathogenic reactive carbonyl species and inhibits the formation of AGEs from Amadori compounds. (Voziyan PA, 2002, Chetyrkin SV, 2008 …”