Premium
Related flavonoids cause cooperative inhibition of the sarcoplasmic reticulum Ca 2+ ATP ase by multimode mechanisms
Author(s) -
Ogunbayo Oluseye A.,
Michelangeli Francesco
Publication year - 2014
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.12621
Subject(s) - galangin , chemistry , quercetin , dephosphorylation , biochemistry , binding site , autophosphorylation , phosphorylation , dissociation constant , atpase , biophysics , mechanism of action , stereochemistry , enzyme , biology , protein kinase a , phosphatase , in vitro , receptor , kaempferol , antioxidant
Flavonoids are group of plant‐derived hydroxylated polycyclic molecules found in fruit and vegetables. They are known to bio‐accumulate within humans and are considered to have beneficial health effects, including cancer chemoprotection. One mechanism proposed to explain this is that they are able to induce apoptosis in cancer cells by inhibiting a variety of kinases and also the Ca 2+ ATP ase. An investigation was undertaken with respect to the mechanism of inhibition for three flavonoids: quercetin, galangin and 3,6 dihydroxyflavone (3,6‐ DHF ). Each inhibited the Ca 2+ ATP ase with K i values of 8.7, 10.3 and 5.4 μ m , respectively, showing cooperative inhibition with n ~ 2. Given their similar structures, the flavonoids showed several differences in their mechanisms of inhibition. All three flavonoids stabilized the ATP ase in the E 1 conformation and reduced [ 32 P]‐ ATP binding. However, both galangin and 3,6‐ DHF increased the affinity of Ca 2+ for the ATP ase by decreasing the Ca 2+ ‐dissociation rate constant, whereas quercetin had little effect. Ca 2+ ‐induced changes in tryptophan fluorescence levels were reduced in the presence of 3,6‐ DHF and galangin (but not with quercetin), indicating that Ca 2+ ‐associated changes within the transmembrane helices are altered. Both galangin and quercetin reduced the rates of ATP ‐dependent phosphorylation and dephosphorylation, whereas 3,6‐ DHF did not. Modelling studies suggest that flavonoids could potentially bind to two sites: one directly where nucleotides bind within ATP binding site and the other at a site close by. We hypothesize that interactions of these two neighbouring sites may account for both the cooperative inhibition and the multimode mechanisms of action seen with related flavonoids.