Structural elucidation of a 2:2 4-ketoaldehyde-amine adduct as a model for lysine-directed cross-linking of proteins by 4-ketoaldehydes.
4-Ketoaldehydes react with lysine-based amines to form the same pyrroles that form in low yield by treatment of proteins with 4-hydroxy-2-alkenals generated endogenously during lipid peroxidation. Since pyrroles are susceptible to oxidative coupling, it has been presumed that the cross-linking of proteins observed for 4-ketoaldehydes involves the intermediacy of the corresponding lysine-derived pyrroles. However, the monoalkylpyrroles generated from simple 4-ketoaldehydes do not exhibit oxidative coupling within the time frame that 4-ketoaldehydes induce substantial protein cross-linking. Model studies have revealed that a side reaction competes with the formation of pyrroles from 4-ketoaldehydes and amines. In this paper, we show that this side reaction involves a non-redox aldol-like condensation process resulting in 2:2 adducts, which have been structurally characterized as isomeric pyrrolo[3.2. 1]azabicyclooctanes. Formation of these 2:2 adducts in competition with pyrrole formation is proposed to represent the major pathway for rapid lysine-dependent cross-linking of proteins by simple 4-ketoaldehydes.
Xu
G
G
Department of Chemistry, Case Western Reserve University, Cleveland, Ohio 44106, USA.
Sayre
L M
LM
D000447:Aldehydes / Q000032:analysis / Q000737:chemistry*; D002855:Chromatography, Thin Layer; D003432:Cross-Linking Reagents / Q000737:chemistry*; D008401:Gas Chromatography-Mass Spectrometry; D008239:Lysine / Q000737:chemistry*; D008744:Methylamines / Q000737:chemistry*; D008956:Models, Chemical; D008968:Molecular Conformation; D015394:Molecular Structure; D011758:Pyrroles / Q000737:chemistry; D012545:Schiff Bases / Q000737:chemistry
D000447:Aldehydes; D003432:Cross-Linking Reagents; D008744:Methylamines; D011758:Pyrroles; D012545:Schiff Bases; C027451:methylamine; C027576:4-hydroxy-2-nonenal; D008239:Lysine