title: An analog of the human albumin N-terminus (Asp-Ala-His-Lys) prevents formation of copper-induced reactive oxygen species.
abstract: 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.
authors.affiliation: Department of Trauma Research, Swedish Medical Center, Englewood, Colorado 80110, USA. dbaror@dmibio.com
authors.forename: D
authors.initials: D
authors.lastname: Bar-Or
authors.forename: L T
authors.initials: LT
authors.lastname: Rael
authors.forename: E P
authors.initials: EP
authors.lastname: Lau
authors.forename: N K
authors.initials: NK
authors.lastname: Rao
authors.forename: G W
authors.initials: GW
authors.lastname: Thomas
authors.forename: J V
authors.initials: JV
authors.lastname: Winkler
authors.forename: R L
authors.initials: RL
authors.lastname: Yukl
authors.forename: R G
authors.initials: RG
authors.lastname: Kingston
authors.forename: C G
authors.initials: CG
authors.lastname: Curtis
mesh_terms: D000418:Albumins / Q000494:pharmacology*; D003300:Copper / Q000494:pharmacology*; D006801:Humans; D017665:Hydroxyl Radical / Q000378:metabolism; D007700:Kinetics; D015227:Lipid Peroxidation; D009842:Oligopeptides / Q000378:metabolism / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000378:metabolism; D017392:Thiobarbituric Acid Reactive Substances / Q000032:analysis
chemical_list: D000418:Albumins; D009842:Oligopeptides; D017382:Reactive Oxygen Species; D017392:Thiobarbituric Acid Reactive Substances; C431583:aspartyl-alanyl-histidyl-lysine; D017665:Hydroxyl Radical; D003300:Copper; D013482:Superoxide Dismutase