Role and Regulation of Glutathione Metabolism in Plasmodium falciparum

Abstract

Malaria in humans is caused by one of five species of obligate intracellular protozoan parasites of the genus Plasmodium. P. falciparum causes the most severe disease and is responsible for 600,000 deaths annually, primarily in Sub-Saharan Africa. It has long been suggested that during their development, malaria parasites are exposed to environmental and metabolic stresses. One strategy to drug discovery was to increase these stresses by interfering with the parasites' antioxidant and redox systems, which may be a valuable approach to disease intervention. Plasmodium possesses two redox systems-the thioredoxin and the glutathione system-with overlapping but also distinct functions. Glutathione is the most abundant low molecular weight redox active thiol in the parasites existing primarily in its reduced form representing an excellent thiol redox buffer. This allows for an efficient maintenance of the intracellular reducing environment of the parasite cytoplasm and its organelles. This review will highlight the mechanisms that are responsible for sustaining an adequate concentration of glutathione and maintaining its redox state in Plasmodium. It will provide a summary of the functions of the tripeptide and will discuss the potential of glutathione metabolism for drug discovery against human malaria parasites.

Mapping Risk of Malaria Transmission in Mainland Portugal Using a Mathematical Modelling Approach

“…Malaria in humans is caused by 5 species of protozoans of the genus Plasmodium [2,3]: Plasmodium falciparum ; Plasmodium ovale ; Plasmodium vivax ; Plasmodium malariae ; and Plasmodium knowlesi [4]. In order for humans to become infected, the protozoans need to be transmitted through the bite of an infected female mosquito of the Anopheles genus.…”

Lipoic acid biosynthesis is essential forPlasmodium falciparumtransmission and influences redox response and carbon metabolism of parasite asexual blood stages

“…The cellular redox balance of Plasmodium parasites is constantly under threat of oxidative stress generated by the metabolic functions of the parasite and by the metabolic activities and defence mechanisms of the host (Becker et al, 2004; Müller, 2015; Nepveu and Turrini, 2013; Patzewitz et al, 2013). Apicoplast-specific redox balance is an integral part of the overall cellular redox steady-state (Biddau et al, 2018; Kehr et al, 2010; Mohring et al, 2017).…”

“…This might not be attributed exclusively to the flux of glycolytic pyruvate to PDC as this was suggested to contribute to a build-up of acetyl-CoA in the organelle (Lim and McFadden, 2010). A possible alternative candidate for LA/DHLA recycling might be the apicoplast-targeted GSH reductase (GR) (Müller, 2015). The GR-mediated reduction of LA was demonstrated in rats, and, in particular, the use of NADPH +H + as an electron donor was described in mitochondrial fractions (Haramaki et al, 1997; Pick et al, 1995).…”

“…Finally, an animal diet that generates an environment rich in reactive oxygen species (ROS) in hepatocytes hosting parasite cells resulted in reduced Plasmodium infection in vivo (Zuzarte-Luís et al, 2017). Despite this importance, and the fact that redox regulation is a fundamental aspect of cellular functions, our understanding of the parasite redox regulatory networks remains limited (Kehr et al, 2010; Müller, 2015).…”

Glutathione-deficient Plasmodium berghei parasites exhibit growth delay and nuclear DNA damage

“…It is possible that P. falciparum is incapable of uptaking sufficient amounts of GSH from the mature RBC to allow parasite survival during the erythrocytic cycle [32, 33]. Furthermore, P. falciparum infected RBC display increased GSH efflux [34], which may result in a decrease in GSH available for parasite uptake.…”