title: Purine import into malaria parasites as a target for antimalarial drug development.
abstract: Infection with Plasmodium species parasites causes malaria. Plasmodium parasites are purine auxotrophs. In all life cycle stages, they require purines for RNA and DNA synthesis and other cellular metabolic processes. Purines are imported from the host erythrocyte by equilibrative nucleoside transporters (ENTs). They are processed via purine salvage pathway enzymes to form the required purine nucleotides. The Plasmodium falciparum genome encodes four putative ENTs (PfENT1-4). Genetic, biochemical, and physiologic evidence suggest that PfENT1 is the primary purine transporter supplying the purine salvage pathway. Protein mass spectrometry shows that PfENT1 is expressed in all parasite stages. PfENT1 knockout parasites are not viable in culture at purine concentrations found in human blood (<10 μM). Thus, PfENT1 is a potential target for novel antimalarial drugs, but no PfENT1 inhibitors have been identified to test the hypothesis. Identifying inhibitors of PfENT1 is an essential step to validate PfENT1 as a potential antimalarial drug target.
authors.affiliation: Department of Physiology and Biophysics, Albert Einstein College of Medicine, Bronx, New York.
authors.forename: I J
authors.initials: IJ
authors.lastname: Frame
authors.forename: Roman
authors.initials: R
authors.lastname: Deniskin
authors.forename: Avish
authors.initials: A
authors.lastname: Arora
authors.forename: Myles H
authors.initials: MH
authors.lastname: Akabas
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage / Q000378:metabolism*; D016503:Drug Delivery Systems / Q000639:trends*; D055808:Drug Discovery / Q000639:trends*; D006801:Humans; D008288:Malaria / Q000188:drug therapy / Q000378:metabolism; D033701:Nucleobase, Nucleoside, Nucleotide, and Nucleic Acid Transport Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010271:Parasites / Q000187:drug effects / Q000378:metabolism; D010963:Plasmodium falciparum / Q000187:drug effects / Q000378:metabolism*; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011687:Purines / Q000378:metabolism*
chemical_list: D000962:Antimalarials; C430711:ENT1 protein, Plasmodium falciparum; D033701:Nucleobase, Nucleoside, Nucleotide, and Nucleic Acid Transport Proteins; D015800:Protozoan Proteins; D011687:Purines; C030985:purine
keywords: drug development; malaria; nucleoside transporter; purines