Genetic diversity and structural analysis of 4-diphosphocytidyl-2C-methyl-D-erythritol kinase (IspE) from Plasmodium falciparum .

Background & objectives: Plasmodium parasite harbours unique methylerythritol phosphate (MEP) pathway which is obligatory for the biosynthesis of isoprenoids. In malaria parasites, the isoprenoids arc indispensable during hepatic, erythrocytic and gametocytic stages. Owing to the criticality of MEP pathway and the potential of its enzymes to act as antimalarial drug target, this study comprehensively investigated the genetic diversity and structural composition of 4-diphosphocytidyl-2C-methyl-D-erythritol kinase (IspE), fourth enzyme of MEP pathway in Indian Plasmodium falciparum (PflspE). Methods: The study employed sequencing, modeling and bioinformatics approaches to examine the genetic diversity and associated structural polymorphism in the PflspE gene amplified from the clinical blood samples collected from seven malaria endemic geographical regions of India. Results: The sequence analysis showed that PflspE gene is highly conserved with 100% sequence identity among all the P falciparum Indian isolates as well as with the PflspE gene of reference strain 3D7. Phylogenetic analysis suggested that PfIspE is highly evolved and differ sufficiently from human orthologue mevalonate kinase gene. Structural modeling studies revealed that PflspE has conserved ATP and CDPME-binding domains. The active site was observed to be relatively rigid in architecture with >60% beta-pleated sheets. Interpretation & conclusion: The results of genetic, phylogeny and modeling studies strengthen the potential of PflspE enzyme as a promising antimalarial drug target.