Plasmodium falciparum ATP4 cation-transporting ATPase (PfATP4)

Plasmodium falciparum ATP4 (PfATP4) is a P-type ATPase located on the plasma membrane of the malaria parasite that serves as a vital sodium-efflux pump [UniProt Q8I0V0; Rottmann et al., 2010, Science]. It is essential for maintaining low intracellular sodium concentrations and regulating cytoplasmic pH, which are critical for the parasite's survival within the sodium-rich environment of the host's erythrocytes [Spillman et al., 2013, Cell Host & Microbe]. When PfATP4 is inhibited, the parasite experiences a rapid and lethal rise in intracellular sodium, leading to osmotic stress and cellular swelling [Spillman et al., 2013; Jimenez-Diaz et al., 2014, PNAS]. This target has gained significant attention because it is the primary site of action for several potent antimalarial drug candidates, including the spiroindolone cipargamin (KAE609) and the dihydroisoquinolone SJ733 [Rottmann et al., 2010; Jimenez-Diaz et al., 2014]. PfATP4 is unique to the parasite and lacks a direct human ortholog, making it an attractive target for selective toxicity [UniProt Q8I0V0; Flannery et al., 2013, J. Med. Chem.]. However, the clinical utility of PfATP4 inhibitors is threatened by the relative ease with which the parasite can develop resistance through various point mutations in the pfatp4 gene [Rottmann et al., 2010; Spillman et al., 2013]. Despite this, PfATP4 remains a cornerstone of modern antimalarial drug discovery due to its rapid parasite-killing kinetics across multiple life-cycle stages [Jimenez-Diaz et al., 2014; Flannery et al., 2013].

Other names

PfATP4P-type Na+-ATPaseSodium-efflux ATPaseE1-E2 ATPasePF3D7_1213500

Inhibition of the P-type ATPase disrupts sodium efflux, causing a rapid increase in intracellular sodium levels, osmotic swelling, and parasite death.