A small molecule chaperone rescues the stability and activity of a cancer-associated variant of NAD(P)H:quinone oxidoreductase 1 in vitro.
Emilia StrandbackWolf-Dieter LienhartAltijana Hromic-JahjefendicBenjamin BourgeoisAnja HöglerDaniel WaltenstorferAndreas WinklerKlaus ZanggerTobias MadlKarl GruberPeter MacherouxPublished in: FEBS letters (2019)
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.
Keyphrases
- small molecule
- amino acid
- wild type
- endothelial cells
- oxidative stress
- heat shock
- endoplasmic reticulum
- squamous cell carcinoma
- papillary thyroid
- radiation therapy
- gene expression
- genome wide
- dna methylation
- young adults
- molecular dynamics simulations
- locally advanced
- copy number
- induced pluripotent stem cells
- squamous cell
- heat stress