TY - JOUR
T1 - A small molecule chaperone rescues the stability and activity of a cancer-associated variant of NAD(P)H:quinone oxidoreductase 1 in vitro
AU - Strandback, Emilia
AU - Lienhart, Wolf-Dieter
AU - Hromic-Jahjefendic, Altijana
AU - Bourgeois, Benjamin
AU - Högler, Anja
AU - Waltenstorfer, Daniel
AU - Winkler, Andreas
AU - Zangger, Klaus
AU - Madl, Tobias
AU - Gruber, Karl
AU - Macheroux, Peter
N1 - © 2019 The Authors. FEBS Letters published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.
PY - 2020
Y1 - 2020
N2 - NAD(P)H:quinone oxidoreductase 1 (NQO1) is a human FAD-dependent enzyme that plays a crucial role in the antioxidant defense system. A naturally occurring single-nucleotide polymorphism (NQO1*2) in the NQO1 gene leads to an amino acid substitution (P187S), which severely compromises the activity and stability of the enzyme. The NQO1*2 genotype has been linked to a higher risk for several types of cancer and poor survival rate after anthracycline-based chemotherapy. In this study, we show that a small molecular chaperone (N-(2-bromophenyl)pyrrolidine-1-sulfonamide) repopulates the native wild-type conformation. As a consequence of the stabilizing effect, the enzymatic activity of the P187S variant protein is strongly improved in the presence of the molecular chaperone in vitro.
AB - NAD(P)H:quinone oxidoreductase 1 (NQO1) is a human FAD-dependent enzyme that plays a crucial role in the antioxidant defense system. A naturally occurring single-nucleotide polymorphism (NQO1*2) in the NQO1 gene leads to an amino acid substitution (P187S), which severely compromises the activity and stability of the enzyme. The NQO1*2 genotype has been linked to a higher risk for several types of cancer and poor survival rate after anthracycline-based chemotherapy. In this study, we show that a small molecular chaperone (N-(2-bromophenyl)pyrrolidine-1-sulfonamide) repopulates the native wild-type conformation. As a consequence of the stabilizing effect, the enzymatic activity of the P187S variant protein is strongly improved in the presence of the molecular chaperone in vitro.
U2 - 10.1002/1873-3468.13636
DO - 10.1002/1873-3468.13636
M3 - Article
C2 - 31605637
SN - 1873-3468
VL - 594
SP - 424
EP - 438
JO - FEBS Letters
JF - FEBS Letters
IS - 3
ER -