title: Choline transport in Leishmania major promastigotes and its inhibition by choline and phosphocholine analogs.
abstract: Phosphatidylcholine is the most abundant phospholipid in the membranes of the human parasite Leishmania. The metabolic pathways leading to its biosynthesis are likely to play a critical role in parasite development and survival and may offer a good target for antileishmanial chemotherapy. Phosphatidylcholine synthesis via the CDP-choline pathway requires transport of the choline precursor from the host. Here, we report the first characterization of choline transport in this parasite, which is carrier-mediated and exhibits Michaelis-Menten kinetics with an apparent K(m) value of 2.5 microM for choline. This process is Na(+)-independent and requires an intact proton gradient to be fully functional. Choline transport into Leishmania is highly specific for choline and is inhibited by the choline carrier inhibitor hemicholinium-3, the channel blocker quinacrine, the antimalarial aminoquinolines quinine and quinidine, the antileishmanial phosphocholine analogs, miltefosine and edelfosine, and by choline analogs, most of which have antimalarial activities. Most importantly, choline analogs kill the promastigote form of the parasite in vitro in the low micromolar range. These results set the stage for the use of choline analogs in antileishmanial chemotherapy and shed new lights on the mechanism of action of the leishmanicidal phosphocholine analogs.
authors.affiliation: Department of Pathology, University of Connecticut Health Center, 263 Farmington Ave., Farmington, CT 06030, USA.
authors.forename: Rachel
authors.initials: R
authors.lastname: Zufferey
authors.forename: Choukri Ben
authors.initials: CB
authors.lastname: Mamoun
mesh_terms: D000255:Adenosine Triphosphate / Q000032:analysis; D000818:Animals; D000981:Antiprotozoal Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001692:Biological Transport; D002794:Choline / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D003470:Culture Media; D003566:Cytidine Diphosphate Choline / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D018320:Leishmania major / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D007896:Leishmaniasis / Q000188:drug therapy; D008018:Life Cycle Stages; D010742:Phospholipid Ethers / Q000494:pharmacology; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D012964:Sodium / Q000378:metabolism; D013379:Substrate Specificity
chemical_list: D000981:Antiprotozoal Agents; D003470:Culture Media; D010742:Phospholipid Ethers; D010767:Phosphorylcholine; C026659:edelfosine; D003566:Cytidine Diphosphate Choline; C039128:miltefosine; D000255:Adenosine Triphosphate; D012964:Sodium; D002794:Choline