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Invasion and Replication Strategies of Pathogenes
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SP A12

Cellular Redox Metabolism in Tropical Malaria


Prof. Dr. med. Katja Becker-Brandenburg
Biochemie der Ernährung (FB 09), Interdisziplinäres Forschungszentrum, JLU Gießen


Summary

The protozoan parasite Plasmodium falciparum is the causative agent of tropical malaria and causes 1-3 million deaths annually worldwide. A balanced redox milieu of the parasite and the human host cell is essential for the successful invasion process and the replication of the parasite. This is demonstrated, for example, by the protection of glucose-6-phosphate dehydrogenase deficient erythrocytes as well as by the fact that reduction equivalents in the form of thioredoxin and glutaredoxin are required for the synthesis of deoxyribonucleotides.
Peroxiredoxins (Prx) are thiol-dependent peroxidases that are involved in the detoxification of reactive oxygen species, as well as signal transduction and differentiation processes. Man and P. falciparum possess six and four different Prx, respectively, that can be subdivided according to their localization, substrate specificity, and their catalytic mechanism. Because P. falciparum neither has a catalase nor a glutathione peroxidase it can be assumed that Prx are important for the detoxification of peroxides in the malaria parasite. During the last years we succeeded in generating and biochemically characterizing four different P. falciparum Prx, a Prx from the closely related parasite Toxoplasma gondii, and twelve further proteins of the thioredoxin- and glutathione system from P. falciparum recombinantly.
Within the scope of this application, the catalytic mechanism and the structure of the different P. falciparum Prx shall be characterized comparatively using 3D molecular modelling, site directed mutagenesis, protein biochemical studies, cryoelectron microscopy, crystallization, and X-ray diffraction analysis. Furthermore, the physiological function of the parasite and erythrocyte Prx shall be studied on the basis of treated and untreated parasite cultures. Methodologically, stage specific differential transcriptome and proteome analyses, knock-out parasites, and pull down assays shall be applied. The aim of the project is to functionally constitute the Prx system of the parasite-host unit and to characterize its interaction with other redox systems.


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