Deciphering Structure, Function and Mechanism of Plasmodium IspD Homologs from Their Evolutionary Imprints

Overview

Journal J Comput Aided Mol Des

Publisher Springer

Specialties Biomedical Engineering
Molecular Biology

Date 2019 Feb 21

PMID 30783866

Citations 4

Authors

P Chellapandi

R Prathiviraj

A Prisilla

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

Over 40 Years of Fosmidomycin Drug Research: A Comprehensive Review and Future Opportunities.

Knak T, Abdullaziz M, Hofmann S, Avelar L, Klein S, Martin M Pharmaceuticals (Basel). 2022; 15(12).

PMID: 36559004 PMC: 9782300. DOI: 10.3390/ph15121553.

A hijack mechanism of Indian SARS-CoV-2 isolates for relapsing contemporary antiviral therapeutics.

Prathiviraj R, Saranya S, Bharathi M, Chellapandi P Comput Biol Med. 2021; 132:104315.

PMID: 33705994 PMC: 7935700. DOI: 10.1016/j.compbiomed.2021.104315.

Genomics insights of SARS-CoV-2 (COVID-19) into target-based drug discovery.

Chellapandi P, Saranya S Med Chem Res. 2020; 29(10):1777-1791.

PMID: 32837137 PMC: 7394272. DOI: 10.1007/s00044-020-02610-8.

Deciphering Molecular Virulence Mechanism of Mycobacterium tuberculosis Dop isopeptidase Based on Its Sequence-Structure-Function Linkage.

Prathiviraj R, Chellapandi P Protein J. 2019; 39(1):33-45.

PMID: 31760575 DOI: 10.1007/s10930-019-09876-x.

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