Elucidation of vitamin B metabolism in the human malaria parasite Plasmodium falciparum and their validation as a target for chemotherapy

Resumo

Pyridoxal phosphate (PLP) and thiamine pyrophosphate (TPP) are cofactors of essential enzymes that are ubiquitous in all organisms. Humans depend on the uptake of vitamins via their diet, whereas fungi, bacteria and plants synthesis these cofactors de novo, which was recently' also reported for the malaria parasite Plasmodium falciparum. Additionally to the de novo syntheses, salvage pathways for B6 and B1 have been identified in P. falciparum, which raises questions about the relevance of this dual vitamin provision and further about the possible role of B6 in quenching oxidative stress as reported for plants. However prior to uptake PLP and TPP need to be dephosphorylated which is proposed to be carried out by a secreted phosphatase. Further vitamins are not solely present within the cytosol, they need to be transported into organelles of the parasite, such as the mitochondrion and the apicoplast. Transportation processes of vitamin B1 will be analysed by keto-acid dehydrogenase complexes and organelle specific vitamin B6 acquisition will be investigated via the cysteine desulphurylase NifS and SufS required for iron-sulphur-cluster formation. Both proteins need an acceptor protein, which is proposed to be dually trafficked into both organelles. In an additional project the novel secreted proteins to the surface of the infected erythrocyte will be analysed for their necessity as well as for their trafficking by applying the SELEX technology, which will be carried out in collaboration with researchers at USP. (AU)