A unique mechanism of curcumin inhibition on F1 ATPase

Abstract ATP synthase (F-ATPase) function depends upon catalytic and rotation cycles of the F 1 sector. Previously, we found that F 1 ATPase activity is inhibited by the dietary polyphenols, curcumin, quercetin, and piceatannol, but that the inhibitory kinetics of curcumin differs from that of the other two polyphenols (Sekiya et al., 2012, 2014). In the present study, we analyzed Escherichia coli F 1 ATPase rotational catalysis to identify differences in the inhibitory mechanism of curcumin versus quercetin and piceatannol. These compounds did not affect the 120° rotation step for ATP binding and ADP release, though they significantly increased the catalytic dwell duration for ATP hydrolysis. Analysis of wild-type F 1 and a mutant lacking part of the piceatannol binding site (γΔ277–286) indicates that curcumin binds to F 1 differently from piceatannol and quercetin. The unique inhibitory mechanism of curcumin is also suggested from its effect on F 1 mutants with defective β–γ subunit interactions (γMet23 to Lys) or β conformational changes (βSer174 to Phe). These results confirm that smooth interaction between each β subunit and entire γ subunit in F 1 is pertinent for rotational catalysis.