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Originally published In Press as doi:10.1074/mcp.M200085-MCP200 on March 15, 2003.
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Molecular & Cellular Proteomics 2:146-155, 2003.
© 2003 by The American Society for Biochemistry and Molecular Biology, Inc.

Research

Proteome Mapping of the Protozoan Parasite Leishmania and Application to the Study of Drug Targets and Resistance Mechanisms*

Jolyne Drummelsmith, Vicky Brochu, Isabel Girard, Nadine Messier and Marc Ouellette{ddagger}

From the Infectious Diseases Research Centre, Laval University, Quebec City, Quebec G1V4G2, Canada

Leishmania is a protozoan parasite responsible for significant morbidity and mortality worldwide. Few parasites have been subjected to proteomic analysis to date, but a genome sequencing project for Leishmania major is currently underway, making these studies possible. Here we present a high resolution proteome for L. major comprising almost 3700 spots, making it the most complete two-dimensional gel representation of a parasite proteome generated to date. We have identified a number of landmark proteins by mass spectrometry and show that several of these are valid for the related species Leishmania donovani infantum. We have also observed several forms and fragments of {alpha}- and ß-tubulins and show that the number and amount of these fragments increase with the age of the parasite culture. Trypanothione reductase (TRYR), which replaces glutathione reductase in trypanosomatid parasites, is an essential protein specific to these parasites and as such is under considerable scrutiny as a drug target. Two-dimensional gel analysis of a L. major strain overexpressing TRYR revealed increased amounts of five spots, all at the predicted molecular weight for TRYR and differing by 0.08 pH units in pI. Mass spectrometry identified four of these as TRYR, leading to the novel suggestion that it could be post-translationally modified. Finally quantitative comparative analysis of a methotrexate-resistant mutant of L. major generated in vitro found that a known primary resistance mediator, the pteridine reductase PTR1, was overexpressed. This constitutes the first proteomic analysis of drug resistance in a parasite and also the clearest identification of a primary drug resistance mechanism using this approach. Together these results provide a framework for further proteomic studies of Leishmania species and demonstrate that these tools are valuable for the essential study of potential drug targets and drug resistance mechanisms.

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


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