TY - JOUR
T1 - Exploiting Electrode Nanoconfinement to Investigate the Catalytic Properties of Isocitrate Dehydrogenase (IDH1) and a Cancer-Associated Variant
AU - Herold, Ryan A.
AU - Reinbold, Raphael
AU - Megarity, Clare F.
AU - Abboud, Martine I.
AU - Schofield, Christopher J.
AU - Armstrong, Fraser A.
N1 - Funding Information:
This work was supported by grants to C.J.S. from Cancer Research UK (C8717/A18245) and the Wellcome Trust (Grant number 106244/Z/14/Z) and to F.A.A. from the EPA Cephalosporin Fund. R.A.H. is grateful for funding from the Clarendon Fund and a Trinity College Birkett Scholarship. R.R. was supported by the Oxford-GSK-Crick Doctoral Programme in Chemical Biology via the Interdisciplinary Bioscience DTP, BBSRC (BB/R506655/1) and GlaxoSmithKline. For the purpose of open access, the authors have applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission.
Publisher Copyright:
© 2021 The Authors. Published by American Chemical Society
PY - 2021/7/8
Y1 - 2021/7/8
N2 - 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.
AB - 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.
U2 - 10.1021/acs.jpclett.1c01517
DO - 10.1021/acs.jpclett.1c01517
M3 - Article
C2 - 34170697
AN - SCOPUS:85109734008
SN - 1948-7185
VL - 12
SP - 6095
EP - 6101
JO - Journal of Physical Chemistry Letters
JF - Journal of Physical Chemistry Letters
ER -
