title: Vacuolar type H+ pumping pyrophosphatases of parasitic protozoa.
abstract: Trans-membrane proton pumping is responsible for a myriad of physiological processes including the generation of proton motive force that drives bioenergetics. Among the various proton pumping enzymes, vacuolar pyrophosphatases (V-PPases) form a distinct class of proton pumps, which are characterised by their ability to translocate protons across a membrane by using the potential energy released by hydrolysis of the phosphoanhydride bond of inorganic pyrophosphate. Until recently, V-PPases were known to be the purview of only plant vacuoles and plasma membranes of phototrophic bacteria. Recent discoveries of V-PPases in kinetoplastid and apicomplexan parasites, however, have expanded our view of the evolutionary reach of these enzymes. The lack of V-PPases in the vertebrate hosts of these parasites makes them potentially excellent targets for developing broad-spectrum antiparasitic agents. This review surveys the current understanding of V-PPases in parasitic protozoa with an emphasis on malaria parasites. Topological predictions suggest remarkable similarity of the parasite enzymes to their plant homologues with 15-16 membrane spanning domains and conserved sequences shown to constitute critical catalytic residues. Remarkably, malaria parasites have been shown to possess two V-PPase genes, one is an apparent orthologue of the canonical plant enzyme, whereas the other is a more distantly related paralogue with homology to a recently identified new class of K+-insensitive plant V-PPases. V-PPases appear to localise both to the plasma membrane and cytoplasmic organelles believed to be acidocalcisomes or polyphosphate bodies. Gene transfer experiments suggest that one of the malarial V-PPases is predominantly localised to the surface of intraerythrocytic parasites. We suggest a model in which V-PPase localised to the malaria parasite plasma membrane may serve as an electrogenic pump utilising pyrophosphate as an energy source, thus sparing the more precious ATP. Searching for V-PPase inhibitors could prove fruitful as a novel means of antiparasitic chemotherapy.
authors.affiliation: Department of Microbiology and Immunology, MCP Hahnemann School of Medicine, Philadelphia, PA 19129, USA. michael.mcintosh@yale.edu
authors.forename: Michael T
authors.initials: MT
authors.lastname: McIntosh
authors.forename: Akhil B
authors.initials: AB
authors.lastname: Vaidya
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002462:Cell Membrane / Q000201:enzymology / Q000235:genetics; D007893:Leishmania donovani / Q000201:enzymology*; D008288:Malaria / Q000188:drug therapy; D008969:Molecular Sequence Data; D010961:Plasmodium / Q000201:enzymology* / Q000235:genetics; D011487:Protein Conformation; D017494:Proton Pumps / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D011755:Pyrophosphatases / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D017386:Sequence Homology, Amino Acid; D014122:Toxoplasma / Q000201:enzymology*; D014345:Trypanosoma / Q000201:enzymology*; D014617:Vacuoles / Q000201:enzymology
chemical_list: D017494:Proton Pumps; D011755:Pyrophosphatases