An analog of the human albumin N-terminus (Asp-Ala-His-Lys) prevents formation of copper-induced reactive oxygen species

Copper mobilization and redox activity form damaging Reactive Oxygen Species (ROS) and are implicated in the pathogenesis of ischemia-reperfusion injury, chronic inflammation, Alzheimer's disease, aging, and Cancer. Protein sequestration of Cu(II) ions has been shown to prevent ROS-generating reactions. The first four Amino acids of the N-terminus of human albumin, Asp-Ala-His-Lys (DAHK), form a tight binding site for Cu(II) ions. We synthesized several analogs, including the enantiomer d-DAHK, to study their effects on copper-induced hydroxyl radical and superoxide formation in the presence of ascorbate. d-DAHK prevented thiobarbituric acid-reactive species (TBARS) formation within physiological and acidic pH ranges (7.5-6.5) and inhibited low-density lipoprotein lipid peroxidation. A d-DAHK/Cu complex exhibited superoxide dismutase-like activity by significantly inhibiting superoxide formation. These in vitro results suggest that d-DAHK may shift the Cu(II)-binding equilibrium from the exchangeable Cu(II) pool to the tightly-bound, nonexchangeable pool, prevent ROS formation, and potentially provide therapeutic benefit for ROS-related diseases.