PhD defence S.S. Bosch

Analysis of the ATCase catalysis within the amino acid metabolism of the human malaria parasite Plasmodium falciparum

Malaria, caused by Plasmodium spp., remains with more than 400.000 deaths per year one of the devastating diseases of our time. Plasmodium falciparum, which causes tropical malaria, is the most dangerous one leading to severe malaria. The aim of the thesis of Soraya Bosch was to evaluate the necessity of the aspartate carbamoyltransferase (ATCase) within the aspartate metabolism of the human malaria parasite Plasmodium falciparum. The respective open reading frame has been identified and was cloned; with the encoded enzyme recombinantly expressed we could get conformational and kinetic insights by crystallization experiments, we could resolve the crystal structure of the enzyme, in “T’ (tense) and “R’ (relaxed) states. Moreover, in this work, we show the importance of the PfATCase for the proliferation of the malaria parasite by mutagenic studies and protein interference experiments.As predicted by bioinformatic tools the protein bears an apicoplast-targeting sequence and therefore its localization was determined here. Furthermore, this work is focusing on the ATCase as a drug target, dose-response experiments and protein interference studies with in vivo parasites, proves our hypothesis and the drugability of the enzyme.

Promotores: Prof.dr. A.S.S. Dömling and Prof.dr. C. Wrenger