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

Emilia Strandback; Wolf-Dieter Lienhart; Altijana Hromic-Jahjefendic; Benjamin Bourgeois; Anja Högler; Daniel Waltenstorfer; Andreas Winkler; Klaus Zangger; Tobias Madl; Karl Gruber; Peter Macheroux

doi:10.1002/1873-3468.13636

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

Emilia Strandback, Wolf-Dieter Lienhart, Altijana Hromic-Jahjefendic, Benjamin Bourgeois, Anja Högler, Daniel Waltenstorfer, Andreas Winkler, Klaus Zangger, Tobias Madl, Karl Gruber, Peter Macheroux

Institut für Biochemie (6480)

Publikation: Beitrag in einer Fachzeitschrift › Artikel › Begutachtung

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.

Originalsprache	englisch
Seiten (von - bis)	424-438
Fachzeitschrift	FEBS Letters
Jahrgang	594
Ausgabenummer	3
DOIs	https://doi.org/10.1002/1873-3468.13636
Publikationsstatus	Veröffentlicht - 2020

Fields of Expertise

Human- & Biotechnology

UN SDGs

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10.1002/1873-3468.13636Lizenz: CC BY 4.0

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Strandback, E., Lienhart, W.-D., Hromic-Jahjefendic, A., Bourgeois, B., Högler, A., Waltenstorfer, D., Winkler, A., Zangger, K., Madl, T., Gruber, K., & Macheroux, P. (2020). A small molecule chaperone rescues the stability and activity of a cancer-associated variant of NAD(P)H:quinone oxidoreductase 1 in vitro. FEBS Letters, 594(3), 424-438. https://doi.org/10.1002/1873-3468.13636

Strandback, E, Lienhart, W-D, Hromic-Jahjefendic, A, Bourgeois, B, Högler, A, Waltenstorfer, D, Winkler, A, Zangger, K, Madl, T , Gruber, K & Macheroux, P 2020, 'A small molecule chaperone rescues the stability and activity of a cancer-associated variant of NAD(P)H:quinone oxidoreductase 1 in vitro', FEBS Letters, Jg. 594, Nr. 3, S. 424-438. https://doi.org/10.1002/1873-3468.13636

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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.",

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AU - Strandback, Emilia

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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

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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.

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