The Plasmodium falciparum 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 Plasmodium falciparum. 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 P. falciparum. Here, we demonstrate that the two P. falciparum PPCSs (PfPPCSs) 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 PfPPCS 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 PfPPCS complex while, at the same time, avoiding the human counterpart, paving the way for additional therapies to combat malaria.