Molecular Target Validation of Aspartate Transcarbamoylase from Plasmodium falciparum by Torin 2

• DOI: 10.1021/acsinfecdis.9b00411
• Publication Date: 2020-03-04T16:55:21Z
• Authors: Soraya S. Bosch; Sergey Lunev; Fernando A. Batista; Marleen Linzke; Thales Kronenberger; Alexander S. S. D...; Matthew R. Groves; Carsten Wrenger
• Keywords: Pyrimidine metabolism; Aspartate carbamoyltransferase

Malaria is a tropical disease that kills about half million people around the world annually. Enzymatic reactions within pyrimidine biosynthesis have been proven to be essential for Plasmodium proliferation. Here we report on essentiality of second enzymatic step pathway, catalyzed by aspartate transcarbamoylase (ATC). Crystallization experiments using double mutant ofPlasmodium falciparum ATC (PfATC) revealed importance mutated residues enzyme catalysis. Subsequently, this was employed in protein interference assays (PIAs), which resulted inhibition parasite proliferation when parasites transfected with were cultivated medium lacking an excess nutrients, including aspartate. Addition 5 or 10 mg/L minimal restored parasites' normal growth rate. In vitro and whole-cell presence compound Torin 2 showed specific activity growth, respectively. silico analyses potential binding mode PfATC. Furthermore, transgenic ATC-overexpressing cell line exhibited 10-fold increased tolerance compared control cultures. Taken together, our results confirm antimalarial 2, suggesting PfATC as target drug promising development novel antimalarials.