Malaria kills over 600,000 people annually. Understanding parasite biology is critical for identifying prospective drug targets. Malaria parasites maintain pyrophosphate (PPi) homeostasis in at least three subcellular compartments-the cytoplasm, mitochondrion, and apicoplast, where PPi is generated through various reactions. While cytoplasmic PPi is known to be degraded by soluble pyrophosphatase, it remains unclear how PPi is metabolized in the organelles of malaria parasites. Here, we discovered that Plasmodium falciparum encodes two soluble pyrophosphatase isoforms from a single genetic locus. The longer isoform contains an N-terminal leader sequence that targets the enzymes into the mitochondrion and the apicoplast. This dual targeting mechanism of soluble pyrophosphatases has not been previously reported in any organisms. We show that both isoforms are essential for parasite growth and development. These findings highlight the critical role of organellar PPi degradation and identify soluble pyrophosphatases as promising antimalarial drug targets.
Nwankwo et al. (Wed,) studied this question.