Characterization of Plasmodium falciparum Adenylyl Cyclase-β and Its Role in Erythrocytic Stage Parasites

The most severe form of human malaria is caused by the parasite Plasmodium falciparum. The second messenger cAMP has been shown to be important for the parasite's ability to infect the host's liver, but its role during parasite growth inside erythrocytes, the stage responsible for symptomatic malaria, is less clear. The P. falciparum genome encodes two adenylyl cyclases, the enzymes that synthesize cAMP, PfAC alpha and PfAC beta. We now show that one of these, PfAC beta, plays an important role during the erythrocytic stage of the P. falciparum life cycle. Biochemical characterization of PfAC beta revealed a marked pH dependence, and sensitivity to a number of small molecule inhibitors. These inhibitors kill parasites growing inside red blood cells. One particular inhibitor is selective for PfAC beta relative to its human ortholog, soluble adenylyl cyclase (sAC); thus, PfAC beta represents a potential target for development of safe and effective antimalarial therapeutics.