Glutathione metabolism in protozoan parasites : making the difference

Abstract

Generation of reactive oxygen species (ROS) is a common feature of abiotic and biotic stresses. ROS need to be detoxified to avoid the occurrence of deleterious reactions. Parasitic diseases such as sleeping sickness, Chagas disease, and malaria, between others, are major health problems in poverty-stricken areas. Redox metabolism in parasitic protozoa is a potentially relevant target for developing specific drug inhibitors. The design of efficacious and safe drugs is possible after the occurrence of metabolic pathways that are unique and essential to the parasite, but absent in the host. In most organisms, glutathione is the most abundant low-molecular weight thiol acting in cellular redox systems. In those parasites with deficit or lacking the glutathione machinery, other active molecules are functional in mimicking the former reductive compound. Many of the known glutathione-dependent processes are directly related to specific life-style of the respective parasite. Thus, malaria parasites have a dual antioxidant system based on glutathione and thioredoxin. Proteins involved in glutathione-dependent metabolic pathways include glutaredoxins, glyoxalases, thioredoxins, glutathione reductase and glutathione S-transferases. In contrast, in trypanosomatids (Trypanosoma and Leishmania spp.), the redox network is centered around trypanothione [N1,N8-bis(glutathionyl)spermidine], instead of the ubiquitous glutathione. In these parasites, trypanothione participates in essential thiol?disulfide exchange reactions as electron donor to different trypanothione-dependent enzymes such as tryparedoxin, glutaredoxin and peroxiredoxins. Since trypanosomatids lack glutathione reductase and thioredoxin reductase, trypanothione is the central node in these microorganisms taking electrons from NADPH to achieve antioxidant enzymes. Concerning some anaerobic parasites such as Entamoeba histolytica or Giardia lamblia, they are human pathogens that lack the capacity to synthesize glutathione, and they have cysteine as the major low-molecular weight thiol. In this chapter, we review the glutathione dependent metabolism in protozoan parasitic cells, pointing out its relevance in vital functions of the parasite. We also comparatively analyze differences and similarities between glutathione and alternative metabolisms in the different protozoa. Particular attention is given to the role of glutathione in redox regulation and adaptation to stresses, highlighting the importance of enzymes belonging to redox metabolism, many of them proposed as target of antiparasitic drugs.