Sodium-transporting ATPase (PfATP4) (PfATP4)

Sodium-transporting ATPase (PfATP4) is a P-type ATPase located on the plasma membrane of the malaria parasite Plasmodium falciparum (UniProt Q8I0V0). It serves as the primary mechanism for exporting sodium ions (Na+) from the parasite's cytoplasm, maintaining a low intracellular Na+ concentration (~10 mM) against a high extracellular gradient (~140 mM) (Vaidya et al., 2014). This ion gradient is essential for the parasite's volume regulation, pH homeostasis, and the function of various secondary transporters. PfATP4 has been identified as the molecular target for several chemically diverse classes of antimalarial drug candidates, most notably the spiroindolones like Cipargamin (KAE609) and dihydroisoquinolones like SJ733 (Rottmann et al., 2010; Jiménez-Díaz et al., 2014). Inhibition of the pump leads to a rapid and lethal accumulation of intracellular sodium, which causes osmotic swelling and parasite death across multiple stages of the life cycle. While PfATP4 is a highly effective target, its clinical utility is challenged by the emergence of resistance-conferring mutations in the pfatp4 gene, which must be closely monitored in clinical settings (Flannery et al., 2013). The distinct structure of PfATP4 compared to human P-type ATPases, such as the Na+/K+-ATPase, provides a therapeutic window for selective inhibition (Spillman et al., 2013).

Other names

P-type Na+-ATPasePlasmodium falciparum ATPase 4Sodium-efflux ATPasePfATP4P-type sodium pump

Inhibition of the PfATP4 pump prevents sodium efflux, leading to a rapid increase in intracellular sodium concentration, osmotic stress, and parasite lysis.