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Originally published In Press as doi:10.1074/jbc.M308352200 on September 27, 2003

J. Biol. Chem., Vol. 278, Issue 50, 49965-49971, December 12, 2003
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Functional Cloning of the Miltefosine Transporter

A NOVEL P-TYPE PHOSPHOLIPID TRANSLOCASE FROM LEISHMANIA INVOLVED IN DRUG RESISTANCE*

F. Javier Pérez-Victoria{ddagger}§, Francisco Gamarro{ddagger}, Marc Ouellette¶||, and Santiago Castanys{ddagger}**

From the {ddagger}Instituto de Parasitología y Biomedicina "López-Neyra," Consejo Superior de Investigaciones Científicas, 18001 Granada, Spain and Centre de Recherche en Infectiologie du Centre de Recherche du CHUL, Université Laval, Sainte Foy, Québec G1V 4G2, Canada

The antitumor drug miltefosine (hexadecylphosphocholine, MIL) has recently been approved as the first oral agent for the treatment of visceral leishmaniasis. Little is known about the mechanisms of action and uptake of MIL in either parasites or tumor cell lines. We have cloned a putative MIL transporter (LdMT) by functional rescue, using a Leishmania donovani-resistant line defective in the inward-directed translocation of both MIL and glycerophospholipids. LdMT is a novel P-type ATPase belonging to the partially characterized aminophospholipid translocase subfamily. Resistant parasites transfected with LdMT regain their sensitivity to MIL and edelfosine and the ability to normally take up [14C]MIL and fluorescent-labeled glycerophospholipids. Moreover, LdMT localizes to the plasma membrane, and its overexpression in Leishmania tarentolae, a species non-sensitive to MIL, significantly increases the uptake of [14C]MIL, strongly suggesting that this protein behaves as a true translocase. Finally, both LdMT-resistant alleles encompass single but distinct point mutations, each of which impairs transport function, explaining the resistant phenotype. These results demonstrate biochemically and genetically the direct involvement of LdMT in MIL and phospholipids translocation in Leishmania and describe for the first time a P-type ATPase involved in MIL uptake and potency in eukaryotic cells.

Received for publication, July 30, 2003 , and in revised form, September 23, 2003.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBankTM/EBI Data Bank with accession number(s) AY321297.

* This work was supported by European Community Grant QLRT-2000-01404 (to F. G.), Spanish Grant SAF2001-4562-E (to F. G.), and Canadian Institutes of Health Research grants (to M. O.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ Recipient of a fellowship from the Ministerio de Educación y Cultura.

|| Holder of a Canada Research Chair in Antimicrobial Resistance and a Burroughs Wellcome Fund Scholar in Molecular Parasitology.

** To whom correspondence should be addressed: Instituto de Parasitología y Biomedicina "López-Neyra," Consejo Superior de Investigaciones Científicas, Ventanilla, 11, 18001 Granada, Spain. Tel.: 34-958-805185; Fax: 34-958-203911; E-mail: castanys{at}ipb.csic.es.


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