Inhibition of the SERCA Ca2+ pumps by curcumin. Curcumin putatively stabilizes the interaction between the nucleotide-binding and phosphorylation domains in the absence of ATP.

Curcumin is a compound derived from the spice, tumeric. It is a potent inhibitor of the SERCA Ca2+ pumps (all isoforms), inhibiting Ca2+-dependent ATPase activity with IC50 values of between 7 and 15 microm. It also inhibits ATP-dependent Ca2+-uptake in a variety of microsomal membranes, although for cerebellar and platelet microsomes, a stimulation in Ca2+ uptake is observed at low curcumin concentrations (<10 microm). For the skeletal muscle isoform of the Ca2+ pump (SERCA1), the inhibition of curcumin is noncompetitive with respect to Ca2+, and competitive with respect to ATP at high curcumin concentrations ( approximately 10-25 microm). This was confirmed by ATP binding studies that showed inhibition in the presence of curcumin: ATP-dependent phosphorylation was also reduced. Experiments with fluorescein 5'-isothiocyanate (FITC)-labelled ATPase also suggest that curcumin stabilizes the E1 conformational state. The fact that FITC labels the nucleotide binding site of the ATPase (precluding ATP from binding), and the fact that curcumin affects FITC fluorescence indicate that curcumin must be binding to another site within the ATPase that induces a conformational change to prevent ATP from binding. This observation is interpreted, with the aid of recent structural information, as curcumin stabilizing the interaction between the nucleotide-binding and phosphorylation domains, precluding ATP binding.