title: Identification and functional analysis of the primary pantothenate transporter, PfPAT, of the human malaria parasite Plasmodium falciparum.
abstract: The human malaria parasite Plasmodium falciparum is absolutely dependent on the acquisition of host pantothenate for its development within human erythrocytes. Although the biochemical properties of this transport have been characterized, the molecular identity of the parasite-encoded pantothenate transporter remains unknown. Here we report the identification and functional characterization of the first protozoan pantothenate transporter, PfPAT, from P. falciparum. We show using cell biological, biochemical, and genetic analyses that this transporter is localized to the parasite plasma membrane and plays an essential role in parasite intraerythrocytic development. We have targeted PfPAT to the yeast plasma membrane and showed that the transporter complements the growth defect of the yeast fen2Δ pantothenate transporter-deficient mutant and mediates the entry of the fungicide drug, fenpropimorph. Our studies in P. falciparum revealed that fenpropimorph inhibits the intraerythrocytic development of both chloroquine- and pyrimethamine-resistant P. falciparum strains with potency equal or better than that of currently available pantothenate analogs. The essential function of PfPAT and its ability to deliver both pantothenate and fenpropimorph makes it an attractive target for the development and delivery of new classes of antimalarial drugs.
authors.affiliation: Department of Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: Yoann
authors.initials: Y
authors.lastname: Augagneur
authors.forename: Lise
authors.initials: L
authors.lastname: Jaubert
authors.forename: Matthieu
authors.initials: M
authors.lastname: Schiavoni
authors.forename: Niseema
authors.initials: N
authors.lastname: Pachikara
authors.forename: Aprajita
authors.initials: A
authors.lastname: Garg
authors.forename: Sahar
authors.initials: S
authors.lastname: Usmani-Brown
authors.forename: Donna
authors.initials: D
authors.lastname: Wesolowski
authors.forename: Skye
authors.initials: S
authors.lastname: Zeller
authors.forename: Abhisek
authors.initials: A
authors.lastname: Ghosal
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Cornillot
authors.forename: Hamid M
authors.initials: HM
authors.lastname: Said
authors.forename: Priti
authors.initials: P
authors.lastname: Kumar
authors.forename: Sidney
authors.initials: S
authors.lastname: Altman
authors.forename: Choukri
authors.initials: C
authors.lastname: Ben Mamoun
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology; D002462:Cell Membrane / Q000378:metabolism*; D002738:Chloroquine / Q000494:pharmacology; D004351:Drug Resistance / Q000187:drug effects; D004912:Erythrocytes / Q000187:drug effects / Q000469:parasitology / Q000648:ultrastructure; D005816:Genetic Complementation Test; D057809:HEK293 Cells; D006790:Host-Parasite Interactions / Q000187:drug effects; D006801:Humans; D016778:Malaria, Falciparum / Q000469:parasitology; D008856:Microscopy, Fluorescence; D016253:Microscopy, Immunoelectron; D008969:Molecular Sequence Data; D009025:Morpholines / Q000378:metabolism / Q000494:pharmacology; D009154:Mutation; D010205:Pantothenic Acid / Q000378:metabolism / Q000494:pharmacology; D010802:Phylogeny; D010963:Plasmodium falciparum / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D015800:Protozoan Proteins / Q000235:genetics / Q000378:metabolism*; D011739:Pyrimethamine / Q000494:pharmacology; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D027981:Symporters / Q000145:classification / Q000235:genetics / Q000378:metabolism*
chemical_list: D000962:Antimalarials; C436246:FEN2 protein, S cerevisiae; D009025:Morpholines; D015800:Protozoan Proteins; D029701:Saccharomyces cerevisiae Proteins; D027981:Symporters; C119982:pantothenate transporter; D010205:Pantothenic Acid; C050435:fenpropimorph; D002738:Chloroquine; D011739:Pyrimethamine
keywords: Drug Delivery; Malaria; Plasmodium; Transport; Yeast