Infoscience

Thesis

Reconstruction and systems analysis of metabolism in apicomplexan parasites Toxoplasma gondii and Plasmodium falciparum

Understanding of metabolism in disease-causing microorganisms promotes drug design through the identification of the enzymes whose activity is indispensable for important cellular functions of the pathogens. Nowadays such understanding arises from experimental as well as computational studies. These two approaches, long considered as rather orthogonal, in recent years began to converge and form a new field, where they are utilized as complementary. In this thesis I present my endeavors in bringing closer the fields of infection and systems biology with a particular focus on large-scale metabolic models and their analysis. Integrative, interdisciplinary nature of my project also included multiple experimental inputs as well as original experimental efforts on investigating model-derived hypotheses. In the scope of this thesis I explored metabolism of two of the most experimentally amenable apicomplexan species – human parasites Plasmodium falciparum and Toxoplasma gondii. As a foundation for the studies included in this thesis I used standard as well as recently developed computational algorithms, existing experimental datasets and innovative context- specific assumptions. I produced an extensive survey of the modeling efforts previously applied for studying metabolism of P. falciparum and available large-scale experimental datasets in comparison with the similar efforts made in other species. Further, I curated an existing model of metabolism in Plasmodium falciparum with respect to an up-to-date primary literature on metabolism of the parasite and addressed several important assumptions implicitly made in this model. Using a state-of-the-art approach, I reconstructed de novo a comprehensive metabolic model of T. gondii, and performed an extensive computational analysis to explore its metabolic needs and capabilities. I identified and classified the minimal set of substrates the parasite utilizes for growth, along with the genes and pairs of genes that are essential for cellular functions such as growth and energy metabolism. Subsequently, several of the model-driven hypotheses were confirmed experimentally, while for validation of the majority of the computational predictions forthcoming high-throughput approaches shall be used. Every confirmed hypothesis expands the scope of our knowledge on peculiarities of metabolism in apicomplexan parasites and hence can serve as an input for the pipeline of developing novel medicines.

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