Membrane-bound inorganic pyrophosphatase 1 (PfVP1) (PfVP1)

Membrane-bound inorganic pyrophosphatase 1 (PfVP1) is an essential proton-pumping enzyme expressed by the malaria parasite Plasmodium falciparum throughout its erythrocytic life cycle [McIntosh et al., 2020]. It functions by coupling the exothermic hydrolysis of inorganic pyrophosphate (PPi) to the translocation of protons across the parasite's plasma membrane and acidocalcisome membranes, thereby maintaining the electrochemical gradient and internal pH necessary for survival [Luo et al., 2016]. Because humans rely exclusively on soluble pyrophosphatases that do not pump protons, PfVP1 represents a highly selective therapeutic target with no host homologs [Jezewski et al., 2020]. Pharmacological inhibition of PfVP1 results in the dual catastrophe of toxic PPi accumulation and the collapse of the proton motive force, which disrupts nutrient uptake and organelle function, ultimately leading to parasite death [McIntosh et al., 2020]. Recent drug discovery efforts, including high-throughput screens by the Medicines for Malaria Venture (MMV), have identified several small-molecule inhibitors that are effective against multidrug-resistant strains of P. falciparum [Gopalan et al., 2022]. As a validated target, PfVP1 is currently a focal point for developing next-generation antimalarials designed to overcome existing resistance to frontline treatments.

Other names

H+-translocating inorganic pyrophosphataseVacuolar-type H+-pyrophosphatase 1V-PPasePyrophosphate-energized inorganic pyrophosphataseK+-stimulated H+-pyrophosphatase

Inhibition of inorganic pyrophosphate hydrolysis and vacuolar proton translocation, leading to toxic pyrophosphate accumulation and dissipation of the proton motive force.