S. S. Bosch, S. Lunev, F. A. Batista
Mar 4, 2020
Citations
1
Influential Citations
7
Citations
Quality indicators
Journal
ACS infectious diseases
Abstract
Malaria is a tropical disease that kills about half a million people around the world annually. Enzymatic reactions within the pyrimidine biosynthesis have been proven to be essential for Plasmodium proliferation. Here we report on the essentiality of the second enzymatic step of the pyrimidine biosynthesis pathway, catalysed by Aspartate Transcarbamoylase (ATC). Crystallisation experiments using a double mutant PfATC revealed the importance of the mutated residues for enzyme catalysis. Subsequently, this mutant has been employed in Protein interference assays (PIA), which resulted in inhibition of parasite proliferation when parasites transfected with the double mutant were cultivated in minimal medium lacking aspartate. In vitro and whole-cell assays in the presence of the compound Torin2 have shown inhibition of specific activity and parasite growth, respectively. In silico analyses revealed the potential binding mode of the compound Torin 2 to PfATC. Furthermore, a transgenic ATC overexpressing cell line exhibited a 10-fold increased tolerance to Torin 2 compared to control cultures. Taken together, our results confirm the antimalarial activity of Torin2, suggesting PfATC as a target of this drug and a promising target for the development of novel antimalarials.