The <i>Plasmodium falciparum</i> PPCS is a unique heteromeric complex with prokaryote-like activity and is a target of pantothenate analogs

Coenzyme A (CoA) is essential for the intraerythrocytic stage of <i>Plasmodium falciparum</i>. Phosphopantothenoylcysteine synthetase (PPCS) catalyzes the second of five steps of the CoA biosynthesis pathway. Most apicomplexan parasites express one PPCS, whereas two PPCSs are expressed in <i>P. falciparum</i>. Here, we demonstrate that the two <i>P. falciparum</i> PPCSs (<i>Pf</i>PPCSs) associate into a single, functional PPCS heteromeric complex that, unlike any other eukaryotic PPCS reported to date, is unable to use adenosine 5'-triphosphate. We identify a prokaryote-like helical component of <i>Pf</i>PPCS as important for the nucleotide specificity and potentially holding the key for its stringency for cytidine 5'-triphosphate. Moreover, we show that the complex is the target of multiple antiplasmodial pantothenate analogs and interacts with other analogs that target different steps in CoA biosynthesis/utilization. Our study provides opportunities for designing inhibitors that exploit the unique features of the <i>Pf</i>PPCS complex while, at the same time, avoiding the human counterpart, paving the way for additional therapies to combat malaria.