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A Bioinformatics Approach for Homology Modeling and Binding Site Identification of Triosephosphate Isomerase from Plasmodium falciparum 3D7.

ABSTRACT: Malaria is a major public health concern, and malarial parasites have developed resistance against the commonly available drugs. So now a days it is a major concern to find out a new target for drug therapy. Plasmodium falciparum 3D7, one of the strains of plasmodium species also lacks in a functional tricarboxylic acid cycle and solely dependent on glycolysis for its energy supply like other plasmodium species. Although enzymes of malarial parasite have been considered as potential antimalarial drug targets, a little is known about their structural biology. The tertiary structure of triose phosphate isomerase of P. falciparum 3D7 was determined by means of homology modeling through multiple alignment followed by intensive optimization and validation. The modeling was done by Swiss-Model Workspace. The obtained model was verified with the structure validation programs such as, PROCHECK, Verify3D, and QMEAN for reliability. The verify3D value of 0.69 indicates that the environment profile of the model is good. A self-optimized prediction method with alignment or SOPMA is employed for calculation of the secondary structural features of triose phosphate isomerase. The secondary structure indicates that the predicted 3D structure of triosephosphate isomerase of P. falciparum 3D7 contains 48.37% ?-helix, 29.27% random coil, and 16.67% extended strand. Active site determination through CASTp suggests that this protein can be utilized as a potential drug target. However, these will further be tested by wet lab studies for a targeted vaccine design against P. falciparum 3D7.

SUBMITTER: Ullah M

PROVIDER: S-EPMC3573378 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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A Bioinformatics Approach for Homology Modeling and Binding Site Identification of Triosephosphate Isomerase from Plasmodium falciparum 3D7.

Ullah M M Hira J J Ghosh T T Ishaque N N Absar N N

Journal of young pharmacists : JYP 20121001 4

Malaria is a major public health concern, and malarial parasites have developed resistance against the commonly available drugs. So now a days it is a major concern to find out a new target for drug therapy. Plasmodium falciparum 3D7, one of the strains of plasmodium species also lacks in a functional tricarboxylic acid cycle and solely dependent on glycolysis for its energy supply like other plasmodium species. Although enzymes of malarial parasite have been considered as potential antimalarial ...[more]

PMID: 23492818

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Project description:BackgroundPlasmodium falciparum is the most virulent parasite of the five Plasmodium species that cause human malaria, and biological analysis of the parasite is critical for the development of novel strategies for disease control. DNA endonucleases are important for maintaining the biological activity, gene stability of the parasite and interaction with host immune systems. In this study, ten sequences of DNA endonucleases were found in the genome of P. falciparum 3D7 clone, seven of them were predicted to contain an endonuclease/exonuclease/phosphatase (IPR005135) domain which plays an important role in DNA catalytic activity. The seven DNA endonucleases of P. falciparum were systematically investigated.MethodsPlasmodium falciparum 3D7 clone was cultured in human O+ RBCs, RNA was extracted at 8, 16, 24, 32, 40, and 48 h post invasion and real-time quantitative PCR was carried out to analyse the transcription of the seven DNA endonuclease genes in asexual stages. Immunofluorescence assay was carried out to confirm the location of the encoded proteins expressed in the erythrocytic stages. Finally, the catalytic activity of the DNA nucleases were tested.ResultsOf the seven proteins analysed, two proteins were not soluble. Fragments derived from the rest five endonuclease sequences were successfully expressed as soluble proteins, and which were used to generate antisera for protein localization. The proteins were all located in the nucleus at ring and trophozoite stages. While at schizont stage, proteins encoded by PF3D7_1238600, PF3D7_0107200 and PF3D7_0319200 were in the punctuated forms in the parasite most likely around nuclei of the merozoites. But the proteins encoded by PF3D7_0305600 and PF3D7_1363500 were distributed around the infected erythrocyte membrane. The enzymatic activity of the recombinant GST-PF3D7_1238600 was very efficient without divalent iron, while the activity of the rest four enzymes was iron dependent. Further, divalent irons did not show any specific enhancement on the activity of GST-PF3D7_1238600, but the activity of GST-PF3D7_0107200, GST-PF3D7_1363500 and GST-PF3D7_0319200 were Cu2+ dependent. The activity of GST-PF3D7_0305600 was dependent on Mg2+ and Mn2+. Except GST-PF3D7_1363500, four of the GST tagged recombinant proteins hydrolysed the supercoiled circular plasmid DNA with or without divalent metal ions. The GST-PF3D7_1363500 protein only changed the supercoiled circular plasmid DNA into nicked plasmids, even with Cu2+.ConclusionsFragments derived from five of the endonuclease sequences of P. falciparum 3D7 clone were successfully expressed. The proteins displayed diverse cell distribution, biochemical and enzymatic activities, which indicated that they carried different biological function in the development of the parasite in the erythrocytes. The DNA repair and DNA degradation capacity of the DNA endonucleases in the biology of the parasite remained further studied.

Dataset Information

A Bioinformatics Approach for Homology Modeling and Binding Site Identification of Triosephosphate Isomerase from Plasmodium falciparum 3D7.

Publications

A Bioinformatics Approach for Homology Modeling and Binding Site Identification of Triosephosphate Isomerase from Plasmodium falciparum 3D7.

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