Independent Synthesis, Solution Behavior, and Studies on the Mechanism of Formation of a Primary Amine-Derived Fluorophore Representing Cross-linking of Proteins by (E)-4-Hydroxy-2-nonenal

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Abstract

Lipid peroxidation in aging and degenerative disease results in the production of 4-hydroxy-2-alkenals that modify proteins and give rise to both protein cross-linking and fluorophore generation. Recent model studies demonstrated that the major ex/em 360/430 fluorophore formed from (E)-4-hydroxy-2-nonenal (HNE) or (E)-4-hydroxy-2-hexenal (HHE) and protein lysine-based amine is a 2-alkyl-2-hydroxy-1,2-dihydropyrrol-3-one iminium 1:2 cross-link (1), a structure that is further confirmed here using 15N-labeling, and which has pH stability characteristics the same as those of lipofuscin pigments isolated from human tissues. Fluorophore generation represents an overall four-electron oxidation, requires dioxygen, and is enhanced by the presence of Cu(II). The HNE−propylamine-derived fluorophore 1a was independently synthesized from either 3,4-dioxononanal (8) or (E)-4-oxo-2-nonenal (13), providing further evidence for its assigned structure and clues to how it forms from HNE. Mechanistic studies on HNE-derived fluorophore formation permit ruling out the initial reversible HNE-derived Schiff base Michael adduct (17) as an intermediate. In addition, the structurally related non-cross-link 2-pentyl-2-hydroxy-1,2-dihydropyrrol-3-one 9a that forms along with 1a from 8 does not form from HNE and does not serve as a precursor to 1a in the HNE−amine reaction system. A mechanism involving two 2e oxidations following initial Schiff base formation is proposed that is consistent with intermediates independently accessed from 8 and 13.

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