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Submitted on December 20, 2002
Centre de Recherche en Infectiologie, Université Laval, Quebec City, Quebec G1V 4G2
Corresponding Author: Marc.Ouellette{at}crchul.ulaval.ca
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 L. 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 L. donovani infantum. We have also observed several forms and fragments of ƒÑ and ƒÒ 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. 2D 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.
Revised on March 15, 2003
Accepted on March 15, 2003
Proteome mapping of the protozoan parasite Leishmania and application to the study of drug targets and resistance mechanisms
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