Deciphering structure, function and mechanism of Plasmodium IspD homologs from their evolutionary imprints
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Malaria is a life-threatening mosquito-borne blood disease caused by infection with Plasmodium parasites. Anti-malarial drug resistance is a global threat to control and eliminate malaria and therefore, it is very important to discover and evaluate new drug targets. The 2-C-methyl-d-erythritol 4-phosphate cytidylyltransferase (IspD) homolog is a second in vivo target for fosmidomycin within isoprenoid biosynthesis in malarial parasites. In the present study, we have deciphered the sequence-structure–function integrity of IspD homologs based on their evolutionary imprints. The function and catalytic mechanism of them were also intensively studied by using sequence-structure homology, molecular modeling, and docking approach. Results of our study indicated that substrate-binding and dimer interface motifs in their structures were extensively conserved and part of them closely related to eubacterial origins. Amino acid substitutions in their coiled-coil regions found to bring a radical change in secondary structural elements, which in turn may change the local structural environment. Arg or Asp was identified as a catalytic site in plasmodium IspD homologs, contributing a direct role in the cytidylyltransferase activity similar to bacterial IspD. Results of molecular docking studies demonstrated how anti-malarial drugs such as fosmidomycin and FR-900098 have competitively interacted with the substrate-binding site of these homologs. As shown by our analysis, species-specific evolutionary imprints in these homologs determine the sequence-structure–function-virulence integrity and binding site alterations in order to confer anti-malarial drug resistance.
KeywordsIspD Fosmidomycin Evolutionary imprints Non-mevalonate pathway Apicoplast Structure–function relationships Drug target
The first author would like to thank Prof. Hemalatha Balaram, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore, India for her outstanding guidance, suggestions, and comments on the present work. The JNCASR visiting-fellowship scheme (JNC/F&E/VF.0102 (LS-01)/2012-715) is duly acknowledged for financial support.
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Conflict of interest
The authors confirm that this article’s content has no conflicts of interest.
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