Copper Exchange and Redox Activity of a Prototypical 8‑Hydroxyquinoline: Implications for Therapeutic Chelation

Mariusz Mital , Izabela A. Zawisza , Magdalena Wiloch , Urszula Wawrzyniak , Vijaya Kenche , Wojciech Wróblewski , Wojciech Bal , Simon C. Drew

Abstract

The N-truncated β-amyloid (Aβ) isoform Aβ4−x is known to bind Cu2+ via a redox-silent ATCUN motif with a conditional Kd = 30 fM at pH 7.4. This study characterizes the Cu2+ 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(NImAβ) was rapid, while the corresponding equilibrium between L and Aβ4−16 occurred slowly via a metastable CuL(NImAβ ) 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 NImAβ ligand will be readily exchangeable with NIm ligands of ubiquitous protein His side chains in vivo, this class of 8HQ ligand could transfer Cu2+ 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
Author Mariusz Mital
Mariusz Mital,,
-
, Izabela A. Zawisza
Izabela A. Zawisza,,
-
, Magdalena Wiloch ZMB
Magdalena Wiloch,,
- Department Of Microbioanalytics
, Urszula Wawrzyniak ZMB
Urszula Wawrzyniak,,
- Department Of Microbioanalytics
, Vijaya Kenche
Vijaya Kenche,,
-
, Wojciech Wróblewski ZMB
Wojciech Wróblewski,,
- Department Of Microbioanalytics
, Wojciech Bal
Wojciech Bal,,
-
, Simon C. Drew
Simon C. Drew,,
-
Journal seriesInorganic Chemistry, ISSN 0020-1669
Issue year2016
Vol55
No15
Pages7317-7319
Publication size in sheets0.3
DOIDOI:10.1021/acs.inorgchem.6b00832
URL http://pubs.acs.org/doi/full/10.1021/acs.inorgchem.6b00832
Languageen angielski
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Copper Exchange and Redox Activity of a Prototypical.pdf 604.54 KB
Score (nominal)45
ScoreMinisterial score = 40.0, 28-11-2017, ArticleFromJournal
Ministerial score (2013-2016) = 45.0, 28-11-2017, ArticleFromJournal
Publication indicators WoS Impact Factor: 2016 = 4.857 (2) - 2016=4.503 (5)
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