Protoplasma (2001) 217:43-49 PROTOPLASMA 9 Springer-Verlag2001 Printed in Austria Thioredoxin and glutathione system of malaria parasite Plasmodium falciparum S. Miiller*, T. W. Gilberger, Z. Krnajski, K. Liiersen, S. Meierjohann, and R. D. Walter Department of Parasite Biochemistry,Bernhard Nocht Institute for Tropical Medicine, Hamburg Received May 5, 2000 Accepted August 12, 2000 Summary. Plasmodium falciparum is the causative agent of malaria tropica. Due to the increasing resistance towards the commonly used plasmodicidal drugs there is an urgent need to identify and assess new targets for the chemotherapeutic intervention of para- site development in the human host. It is established that P. falciparum-infected erythrocytes are vulnerable to oxidative stress, and therefore efficient antioxidative systems are required to ensure parasite development within the host cell. The thioredoxin and glu- tathione redox systems represent two powerful means to detoxify reactive oxygen species and this article summarizes some of the recent work which has led to a better understanding of these systems in the parasite and will help to assess them as potential targets for the development of new chemotherapeutics of malaria. Keywords: Thioredoxin; Glutathione; Plasmodium falciparum; Malaria; Oxidative stress. Abbreviation: BSO L-buthionine-(S,R)-sulphoximine. Introduction Plasmodium falciparum is the causative agent of malaria tropica, one of the most devastating diseases in the tropical regions of the world. Due to an increas- ing resistance towards the commonly used plasmodi- cidal drugs, particularly chloroquine, there is an urgent need to identify and assess new targets for the chemotherapeutic intervention of parasite develop- ment in the human host. For part of its complex life cycle the protozoan parasite resides in human erythrocytes. These devel- opmental stages are responsible for most of the patho- physiology of the disease and the destruction of these * Correspondence and reprints: Department of Parasite Biochem- istry, Bernhard Nocht Institute for Tropical Medicine, Bernhard- Nocht-Strasse 74, 20359 Hamburg, Federal Republic of Germany. parasite stages is one of the goals of our studies. The rationale to focus on the analyses of the two major redox systems in the parasites appears feasible because P. falciparum-infected erythrocytes are under enhanced oxidative stress and are extremely suscep- tible to oxidative challenge (Clark and Hunt 1983, Wozencraft 1986, Vennerstrom and Eaton 1988). The disruption of the parasites' antioxidative systems thus may be a potent way to inhibit their development and survival in the host cell. Thioredoxin system The thioredoxin system consists of the NADPH- dependent oxidoreductase thioredoxin reductase and the small protein thioredoxin. As shown in Fig. 1, reduced thioredoxin transfers reducing equivalents to proteins such as ribonucleotide reductase (Holmgren 1977, 1985) or thioredoxin-dependent peroxidases (Chae et al. 1994, Cha et al. 1995, Kang et al. 1998) and is therefore involved in DNA synthesis and detoxifi- cation of reactive oxygen species. Another task of thioredoxin appears to be the reduction of transcrip- tion factors and thus this system is also involved in redox-signalling processes (Hirota et al. 1997, Jin et al. 1997, Demple 1998, Ding and Demple 1998). Thioredoxin reductase from R falciparum Thioredoxin reductase is a widely distributed flavo- protein which catalyzes the NADPH-dependent reduction of the small protein thioredoxin. Over the past years it became obvious that there exist two forms