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FEBS Lett. 2020 Feb;594(3):424-438. doi: 10.1002/1873-3468.13636. Epub 2019 Oct 30.

A small molecule chaperone rescues the stability and activity of a cancer-associated variant of NAD(P)H:quinone oxidoreductase 1 in vitro.

Author information

1
Institute of Biochemistry, Graz University of Technology, Austria.
2
Institute of Molecular Biosciences, University of Graz, Austria.
3
Department of Genetics and Bioengineering, Faculty of Engineering and Natural Sciences, International University of Sarajevo, Sarajevo, Bosnia and Herzegovina.
4
Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Molecular Biology and Biochemistry, Medical University of Graz, Austria.
5
Institute of Chemistry, University of Graz, Austria.
6
BioTechMed-Graz, Austria.

Abstract

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.

KEYWORDS:

cancer; chemical chaperone; chemotherapeutics; quinone; single-nucleotide polymorphism

PMID:
31605637
DOI:
10.1002/1873-3468.13636

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