Model studies on the metal-catalyzed protein oxidation: structure of a possible His-Lys cross-link.
Redox active transition metals such as copper and iron contribute to biomacromolecular damage that occurs during oxidative stress in a number of degenerative disorders and results in protein cross-linking. On the basis of suggestive evidence for an oxyradical-induced cross-linking between His and Lys side chains, we investigated the Cu(II)-catalyzed oxidation of 4-alkylimidazoles in the presence of amines, as surrogates for these amino acid side chains, using ascorbic acid as a continual source of reducing equivalents. A model His-Lys cross-link was isolated and structurally characterized as a 5-alkyl-5-hydroxy-4-(alkylamino)-1,5-dihydroimidazol-2-one by NMR and mass spectrometry. Evidence that the 2-imidazolone, the principal oxidation product found in the absence of amine, is an intermediate in the formation of the imidazole-amine adduct was that higher yields of the cross-link adduct were obtained starting with the 2-imidazolone. Possible mechanisms for formation of the cross-link and other observed products are discussed.
Liu
Yahua
Y
Department of Chemistry, Case Western Reserve University, Cleveland, Ohio 44106, USA.
Sun
Gang
G
David
Adrian
A
Sayre
Lawrence M
LM
D001205:Ascorbic Acid; D002384:Catalysis; D002851:Chromatography, High Pressure Liquid; D003300:Copper; D003432:Cross-Linking Reagents; D006639:Histidine / Q000737:chemistry*; D017665:Hydroxyl Radical; D007093:Imidazoles / Q000737:chemistry*; D008239:Lysine / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D015394:Molecular Structure; D010084:Oxidation-Reduction; D011506:Proteins / Q000737:chemistry*
D003432:Cross-Linking Reagents; D007093:Imidazoles; D011506:Proteins; D017665:Hydroxyl Radical; D006639:Histidine; D003300:Copper; D008239:Lysine; D001205:Ascorbic Acid