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Exploration of the Atypical Regions of the Plasmodium falciparum Apicoplast DNA Polymerase and Their Potential Role in Antimalarial Drug Discovery

Plasmodium falciparum, the primary cause of malaria in humans, contains a plastid‐like organelle called the apicoplast. The apicoplast exists in most parasitic members of the phylum Apicomplexa and has its own genome along with organelle‐specific enzymes for DNA replication and repair. The only DNA polymerase in the apicoplast, apPOL, is an atypical A‐family polymerase. We solved the crystal structure of P. falciparum apPOL, the first atypical A‐family polymerase to be structurally characterized. apPOL diverges from typical members in two of three previously identified signature motifs and a region not implicated by sequence. Moreover, apPOL has an additional N‐terminal subdomain that may bind DNA, participate in protein‐protein interactions, and/or stabilize its DNA proofreading domain. These structural variances may account for functional differences in polymerase activity. The structure of apPOL also provides a point of departure for structure‐based antimalarial drug design and these atypical regions could be targeted for potent and specific inhibitors. Since apPOL has no direct orthologs to mammalian polymerases, P. falciparum apPOL is an attractive anti‐malarial drug target that provides structural and biochemical insight into a poor characterized subgroup of A‐family polymerases.