Apicoplast DNA polymerase (apPOL)

The apicoplast DNA polymerase (apPOL) is an essential enzyme in Plasmodium parasites, responsible for the replication and repair of the 35 kb circular genome within the apicoplast, a non-photosynthetic plastid organelle [1, 4]. As the sole DNA polymerase localized to this organelle, apPOL is a multitasking enzyme that performs both high-fidelity replicative synthesis and lesion bypass synthesis [12, 16]. It belongs to the A-family of DNA polymerases but is evolutionarily distinct from human polymerases, sharing closer homology with bacterial and cyanobacterial enzymes [1, 5]. Because the apicoplast is vital for the biosynthesis of essential metabolites like isoprenoids, heme, and fatty acids, inhibition of apPOL leads to the loss of the organelle and eventual parasite death [1, 11]. This process is often characterized by a "delayed death" phenotype, where the parasite survives one division cycle before succumbing [1, 2]. The lack of a direct human ortholog makes apPOL a highly attractive target for the development of novel antimalarial drugs, with small molecules like MMV666123 identified as potent and selective inhibitors [3, 9]. Structural studies using cryo-electron microscopy have revealed unique conformational changes and potential allosteric sites that could be exploited for drug design [4, 20].

Other names

apPolPOM1PfPREX polymerase domainPlastidic A-family DNA polymeraseDNA polymerase I-like protein

Inhibition of apicoplast DNA replication and repair, leading to the loss of the apicoplast organelle and subsequent parasite death.