Open AccessExploiting Electrode Nanoconfinement to Investigate the Catalytic Properties of Isocitrate Dehydrogenase (IDH1) and a Cancer-Associated Variant
Author(s) -
Ryan A. Herold,
Raphael Reinbold,
Clare F. Megarity,
Martine I. Abboud,
Christopher J. Schofield,
Fräser A. Armstrong
Publication year - 2021
Publication title -
the journal of physical chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.563
H-Index - 203
ISSN - 1948-7185
DOI - 10.1021/acs.jpclett.1c01517
Subject(s) - isocitrate dehydrogenase , idh1 , chemistry , dissociation (chemistry) , electrode , redox , dehydrogenase , enzyme , biochemistry , biophysics , inorganic chemistry , biology , mutation , gene
Human isocitrate dehydrogenase (IDH1) and its cancer-associated variant (IDH1 R132H) are rendered electroactive through coconfinement with a rapid NADP(H) recycling enzyme (ferredoxin-NADP + reductase) in nanopores formed within an indium tin oxide electrode. Efficient coupling to localized NADP(H) enables IDH activity to be energized, controlled, and monitored in real time, leading directly to a thermodynamic redox landscape for accumulation of the oncometabolite, 2-hydroxyglutarate, that would occur in biological environments when the R132H variant is present. The technique enables time-resolved, in situ measurements of the kinetics of binding and dissociation of inhibitory drugs.