A post-Amadori inhibitor pyridoxamine also inhibits chemical modification of proteins by scavenging carbonyl intermediates of carbohydrate and lipid degradation.
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 post-Amadori 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(epsilon)-(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.
Voziyan
Paul A
PA
Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, Kansas 66160, USA. pvoziyan@kumc.edu
Metz
Thomas O
TO
Baynes
John W
JW
Hudson
Billy G
BG
D000079:Acetaldehyde / Q000031:analogs & derivatives* / Q000737:chemistry*; D016166:Free Radical Scavengers / Q000737:chemistry*; D017127:Glycation End Products, Advanced / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006037:Glyoxal / Q000737:chemistry*; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D011506:Proteins / Q000187:drug effects / Q000378:metabolism*; D011733:Pyridoxamine / Q000737:chemistry*; D012260:Ribonucleases / Q000037:antagonists & inhibitors / Q000378:metabolism; D012710:Serum Albumin, Bovine / Q000378:metabolism; D021241:Spectrometry, Mass, Electrospray Ionization; D013053:Spectrophotometry
D016166:Free Radical Scavengers; D017127:Glycation End Products, Advanced; D011506:Proteins; D012710:Serum Albumin, Bovine; D006037:Glyoxal; D011733:Pyridoxamine; D012260:Ribonucleases; D000079:Acetaldehyde; C010972:glycolaldehyde