A small molecule chaperone rescues the stability and activity of a cancer-associated variant of NAD(P)H:quinone oxidoreductase 1 in vitro
| Autor: | Emilia, Strandback, Wolf-Dieter, Lienhart, Altijana, Hromic-Jahjefendic, Benjamin, Bourgeois, Anja, Högler, Daniel, Waltenstorfer, Andreas, Winkler, Klaus, Zangger, Tobias, Madl, Karl, Gruber, Peter, Macheroux |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
quinone
Protein Conformation chemotherapeutics Drug Evaluation Preclinical single‐nucleotide polymorphism Ligands chemical chaperone Enzyme Activation Molecular Docking Simulation Neoplasms Enzyme Stability Mutation NAD(P)H Dehydrogenase (Quinone) Enzymology cancer Mutant Proteins Amino Acid Sequence Research Articles Research Article |
| Zdroj: | Febs Letters |
| ISSN: | 1873-3468 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Plný text