Plasmodium falciparum 2-C-methyl-D-erythritol 4-phosphate cytidylyltransferase (IspD) (PfIspD)

Plasmodium falciparum IspD (PfIspD), also known as 2-C-methyl-D-erythritol 4-phosphate cytidylyltransferase, is a vital enzyme in the non-mevalonate (MEP) pathway of isoprenoid biosynthesis (UniProt Q8I0U8). This pathway is essential for the survival of the malaria parasite, as it produces precursors for the synthesis of various isoprenoids required for protein prenylation and apicoplast function (PubMed: 21844355). PfIspD specifically catalyzes the CTP-dependent conversion of MEP into 4-diphosphocytidyl-2-C-methyl-D-erythritol (CDP-ME). A key therapeutic advantage of targeting PfIspD is that the MEP pathway is entirely absent in humans, who instead utilize the mevalonate pathway for isoprenoid production (PubMed: 25605917). This fundamental difference allows for the design of highly selective inhibitors with low potential for host toxicity. Compounds such as MMV008138 have demonstrated potent antimalarial activity by targeting this enzyme, making it a high-priority candidate for drug discovery against drug-resistant Plasmodium strains (PubChem CID 53394155). The enzyme's structure has been characterized, facilitating structure-based drug design efforts to overcome emerging resistance (PubMed: 24911122). Inhibition of PfIspD leads to a rapid arrest of parasite growth during the intraerythrocytic stage of the life cycle.

Other names

4-diphosphocytidyl-2-C-methyl-D-erythritol synthaseMEP cytidylyltransferaseCMSIspDPfIspD

Inhibition of the conversion of 2-C-methyl-D-erythritol 4-phosphate (MEP) to 4-diphosphocytidyl-2-C-methyl-D-erythritol (CDP-ME) in the non-mevalonate pathway.