Modulation of the growth of Plasmodium falciparum in vitro by protein serine/threonine phosphatase inhibitors.

To elucidate the physiological roles of the protein serine/threonine phosphatases of P. falciparum, first we identified and characterized phosphatase activities of Plasmodium falciparum enzymologically and pharmacologically. We have demonstrated that P. falciparum possesses phosphatase-1-like activities predominantly over phosphatase-2A-like activities, while erythrocytes possess mainly phosphatase-2A-like activities. Then, we examined the effects of okadaic acid and calyculin A, potent inhibitors of protein phosphatase 1 and 2A, on the growth of P. falciparum in vitro. Both of the drugs inhibited parasite growth dose dependently. The manner of growth inhibition by calyculin A and okadaic acid suggested that these drugs inhibit parasite growth mainly by inhibiting parasite phosphatase-1-like activities. Both drugs were shown to inhibit the growth of three different developmental stages of parasites--ring forms, trophozoites, and schizonts--and inhibit trophozoites the most. This is the first report on P. falciparum protein serine/threonine phosphatase activities, which are essential to regulate the erythrocytic stage of parasite growth.