Redox regulation of protein functions in the plastid of Toxoplasma gondii

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All humans and animals are made of billions of microscopic units named cells. Some organisms, like the parasites we study in this project, comprise only a single cell. Cells are themselves divided into compartments. This division allows proteins, the cell's "workers", to perform their functions in parts of the cell where the conditions are the most suitable for their task. Thus, cell partitioning into compartments with specialized conditions is necessary for proper cell function.An important factor affecting the conditions within each sub-cellular compartment is the balance between chemicals that "oxidize" proteins, namely that take away electrons from them, and chemicals that "reduce" proteins, namely that give proteins electrons. This balance is collectively named "redox". The adjustment of protein function to the redox conditions in the compartment where they work is a crucial cellular control mechanism and if it goes wrong, the cell or the whole animal may die.The key factors that mediate between the redox conditions in a compartment and the activity of the proteins in that compartment are specialized molecules called thioredoxins (Trxs). Trxs react to the compartment's redox conditions by altering the activity of proteins that work in that compartment. The single-celled parasites that are the focus on this study are named apicomplexan parasites. Apicomplexans are harmful parasites causing diseases such as malaria and toxoplasmosis, which kill or cause disabilities to millions of people in the UK and worldwide annually. The ability of these parasites to cause disease depends on a unique structure found only in these parasites - called the apicoplast - without which the parasites cannot survive.The apicoplast comprises four compartments in the parasite cell. We hypothesize that special Apicoplast Trxs (ATrxs) in each of these compartments control the activity of other proteins in them; and that these ATrxs will be essential for the apicoplast functions that are critical to the parasites' survival.We started testing this hypothesis in an apicomplexan parasite named Toxoplasma gondii. We discovered two apicoplast activities that are regulated by ATrxs. Our work further found that one of the ATrxs has unique features that are not found in human Trxs, so it is now being studied as a new drug target for malaria. However, with drug-discovery being a particularly unpredictable process, we believe that to maximise the chances of success we should identify as many potential drug target candidates, operating in the same pathway, as possible. There is every reason to believe that other players of the redox regulatory network of apicoplast functions will also be essential, unique to these parasites and promising candidate for drug targets.We have identified total of seven ATrxs which we expect to regulate many proteins in the apicoplast. We propose to identify the proteins in the apicoplast that are regulated by these new ATrxs and to characterize the roles of each of the ATrxs in this critical regulatory mechanism. This work will enhance the understanding of how this unique and essential parasite structure works. The knowledge that will be generated will likely continue to seed drug discovery for apicomplexans.You can read more about the importance of this project and about the work that we did leading to this project and already published in "the conversation": http://theconversation.com/finding-the-achilles-heel-of-the-cat-parasite-could-mean-more-effective-treatment-for-toxoplasmosis-and-malaria-92232