title: Characterization of 4-hydroxy-3-methylbut-2-en-1-yl diphosphate synthase (IspG) from Plasmodium vivax and it's potential as an antimalarial drug target.
abstract: The prokaryotic type Methyl Erythritol phosphate (MEP) pathway functional in the apicoplast of Plasmodium is indispensable for the erythrocytic stages of the parasite. It is the sole process of isoprenoids biosynthesis in the parasite and is different from that in humans. Among the seven enzymes known to be functional in the MEP pathway in prokaryotes, most enzymes from Plasmodium are yet uncharacterized. The penultimate enzyme of this pathway 4-hydroxy-3-methylbut-2-en-1-yl diphosphate synthase (IspG), has been shown to act as a key target molecule in prokaryotes, where its deletion results in impairment of many housekeeping functions. The present study is the first detailed report of IspG enzyme from any Plasmodium sp. We report here that the protein is highly conserved across apicomplexans and prokaryotes and it localizes to the apicoplast as evident from the immune-localization studies performed on P. vivax infected blood smears made from clinical patients. The biochemical reconstitution and in silico docking of [4Fe-4S] clusters on the protein indicate their importance for the activity of enzyme. In-silico screening of different drug entities suggested the inhibitory role of alkyne diphosphate analogues and fosmidomycin against the IspG enzyme, suggesting the potential role of this enzyme as an antimalarial target.
authors.affiliation: Department of Biological Sciences, Birla Institute of Technology and Science, Pilani, Rajasthan, India.
authors.forename: Gagandeep Singh
authors.initials: GS
authors.lastname: Saggu
authors.affiliation: Department of Biological Sciences, Birla Institute of Technology and Science, Pilani, Rajasthan, India.
authors.forename: Shilpi
authors.initials: S
authors.lastname: Garg
authors.affiliation: Department of Biological Sciences, Birla Institute of Technology and Science, Pilani, Rajasthan, India.
authors.forename: Zarna Rajeshkumar
authors.initials: ZR
authors.lastname: Pala
authors.affiliation: Central Animal Facility, Dept. of Pharmacy, Birla Institute of Technology and Science, Pilani, Rajasthan, India.
authors.forename: Sushil Kumar
authors.initials: SK
authors.lastname: Yadav
authors.affiliation: Department of Medicine, Sardar Patel Medical College, Bikaner, Rajasthan, India.
authors.forename: Sanjay Kumar
authors.initials: SK
authors.lastname: Kochar
authors.affiliation: Department of Medicine, Rajasthan University of Health Sciences, Jaipur, Rajasthan, India.
authors.forename: Dhanpat Kumar
authors.initials: DK
authors.lastname: Kochar
authors.affiliation: Department of Biological Sciences, Birla Institute of Technology and Science, Pilani, Rajasthan, India. Electronic address: vishalsaxena12@gmail.com.
authors.forename: Vishal
authors.initials: V
authors.lastname: Saxena
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000737:chemistry / Q000378:metabolism*; D000962:Antimalarials / Q000378:metabolism / Q000494:pharmacology*; D017124:Conserved Sequence; D006801:Humans; D007501:Iron / Q000378:metabolism; D062105:Molecular Docking Simulation; D058990:Molecular Targeted Therapy; D010966:Plasmodium vivax / Q000187:drug effects* / Q000201:enzymology*; D000072417:Protein Domains; D017421:Sequence Analysis; D013455:Sulfur / Q000378:metabolism
chemical_list: D000962:Antimalarials; D013455:Sulfur; D007501:Iron; D019883:Alkyl and Aryl Transferases
keywords: Apicoplast; GcpE/IspG; MEP isoprenoids biosynthesis pathway