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J. Biol. Chem., Vol. 279, Issue 32, 33273-33280, August 6, 2004

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Differential Protein Expression Analysis of Leishmania major Reveals Novel Roles for Methionine Adenosyltransferase and S-Adenosylmethionine in Methotrexate Resistance^*

Jolyne Drummelsmith, Isabelle Girard, Nathalie Trudel, and Marc Ouellette

From the Infectious Diseases Research Centre, Laval University, Quebec City, Quebec G1V 4G2, Canada

Leishmania is a trypanosomatid parasite causing serious disease and displaying resistance to various drugs. Here, we present comparative proteomic analyses of Leishmania major parasites that have been either shocked with or selected in vitro for high level resistance to the model antifolate drug methotrexate. Numerous differentially expressed proteins were identified by these experiments. Some were associated with the stress response, whereas others were found to be overexpressed due to genetic linkage to primary resistance mediators present on DNA amplicons. Several proteins not previously associated with resistance were also identified. The role of one of these, methionine adenosyltransferase, was confirmed by gene transfection and metabolite analysis. After a single exposure to low levels of methotrexate, L. major methionine adenosyltransferase transfectants could grow at high concentrations of the drug. Methotrexate resistance was also correlated to increased cellular S-adenosylmethionine levels. The folate and S-adenosylmethionine regeneration pathways are intimately connected, which may provide a basis for this novel resistance phenotype. This thorough comparative proteomic analysis highlights the variety of responses required for drug resistance to be achieved.

Received for publication, May 10, 2004 , and in revised form, June 4, 2004.

^* This work was supported by a Canadian Institutes of Health Research (CIHR) fellowship (to J. D.) and CIHR group and operating 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.

A Burroughs Wellcome Fund Scholar in Molecular Parasitology. This author holds a Canada Research Chair in antimicrobial resistance. To whom correspondence should be addressed: Infectious Diseases Research Centre, CHUQ, pavillon CHUL, 2705 Boul. Laurier, Ste.-Foy, QC, G1V 4G2. Tel.: 418-654-2705; Fax: 418-654-2715; E-mail: marc.ouellette{at}crchul.ulaval.ca.

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