title: Copper Exchange and Redox Activity of a Prototypical 8-Hydroxyquinoline: Implications for Therapeutic Chelation.
abstract: The N-truncated β-amyloid (Aβ) isoform Aβ4-x is known to bind Cu(2+) via a redox-silent ATCUN motif with a conditional Kd = 30 fM at pH 7.4. This study characterizes the Cu(2+) interactions and redox activity of Aβx-16 (x = 1, 4) and 2-[(dimethylamino)-methyl-8-hydroxyquinoline, a terdentate 8-hydroxyquinoline (8HQ) with a conditional Kd(CuL) = 35 pM at pH 7.4. Metal transfer between Cu(Aβ1-16), CuL, CuL2, and ternary CuL(NIm(Aβ)) was rapid, while the corresponding equilibrium between L and Aβ4-16 occurred slowly via a metastable CuL(NIm(Aβ)) intermediate. Both CuL and CuL2 were redox-silent in the presence of ascorbate, but a CuL(NIm) complex can generate reactive oxygen species. Because the NIm(Aβ) ligand will be readily exchangeable with NIm ligands of ubiquitous protein His side chains in vivo, this class of 8HQ ligand could transfer Cu(2+) from inert Cu(Aβ4-x) to redox-active CuL(NIm). These findings have implications for the use of terdentate 8HQs as therapeutic chelators to treat neurodegenerative disease.
authors.affiliation: Florey Department of Neuroscience and Mental Health, The University of Melbourne , Melbourne, Victoria 3010, Australia.|Institute of Biochemistry and Biophysics, Polish Academy of Sciences , Warsaw 02-106, Poland.
authors.forename: Mariusz
authors.initials: M
authors.lastname: Mital
authors.affiliation: Institute of Biochemistry and Biophysics, Polish Academy of Sciences , Warsaw 02-106, Poland.
authors.forename: Izabela A
authors.initials: IA
authors.lastname: Zawisza
authors.affiliation: Department of Microbioanalytics, Faculty of Chemistry, Warsaw University of Technology , Warsaw 00-664, Poland.
authors.forename: Magdalena Z
authors.initials: MZ
authors.lastname: Wiloch
authors.affiliation: Department of Microbioanalytics, Faculty of Chemistry, Warsaw University of Technology , Warsaw 00-664, Poland.
authors.forename: Urszula E
authors.initials: UE
authors.lastname: Wawrzyniak
authors.affiliation: Florey Department of Neuroscience and Mental Health, The University of Melbourne , Melbourne, Victoria 3010, Australia.
authors.forename: Vijaya
authors.initials: V
authors.lastname: Kenche
authors.affiliation: Department of Microbioanalytics, Faculty of Chemistry, Warsaw University of Technology , Warsaw 00-664, Poland.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Wróblewski
authors.affiliation: Institute of Biochemistry and Biophysics, Polish Academy of Sciences , Warsaw 02-106, Poland.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Bal
authors.affiliation: Florey Department of Neuroscience and Mental Health, The University of Melbourne , Melbourne, Victoria 3010, Australia.
authors.forename: Simon C
authors.initials: SC
authors.lastname: Drew
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism*; D003300:Copper / Q000737:chemistry / Q000378:metabolism*; D004578:Electron Spin Resonance Spectroscopy; D006801:Humans; D007700:Kinetics; D010084:Oxidation-Reduction; D015125:Oxyquinoline / Q000737:chemistry*; D011804:Quinolines / Q000737:chemistry* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000737:chemistry
chemical_list: D016229:Amyloid beta-Peptides; D011804:Quinolines; D017382:Reactive Oxygen Species; D015125:Oxyquinoline; D003300:Copper