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New Delhi, India

Helicases are enzymes which catalyze the unwinding of nucleic acid substrate in an energy-dependent manner. these are characterized by the presence of nine well defined conserved motifs and are essential for almost all the processes involving nucleic acids. Plasmodium falciparum causes the most virulent form of malaria. The control of malaria is becoming complicated due to the spread of resistance of both the mosquito vector and the parasite to insecticides and anti-malarial drugs. Helicases could be used as feasible drug target for control of malaria. the P. falciparum genome is completely sequenced but the annotation is still in progress. To identify members of various well defined helicase families, I used the bioinformatics approach and helicase domain sequences to search the P. falciparum genome sequence database. In addition to the homologues for a number of human helicases, some novel parasite specific helicases were also identified. I describe the members of DEAD-box, DEAH box, RuvB, Superkiller family, RecQ and repair helicases from P. falciparum. the detailed studies of these helicases will help in identifying a specific enzyme, which could be used as potential target to control the replication and transmission of the malaria parasite. © 2010 Landes Bioscience. Source

Tuteja R.,Malaria Group
Communicative and Integrative Biology | Year: 2013

Malaria is still a devastating disease caused by the mosquito-transmitted parasite Plasmodium, particularly Plasmodium falciparum. During the last few years the situation has worsened in many ways, mainly due to malarial parasites becoming increasingly resistant to several anti-malarial drugs. Thus there is an urgent need to find alternate ways to control malaria and therefore it is necessary to identify new drug targets and new classes of anti-malarial drugs. A malaria vaccine would be the ultimate weapon to fight this deadly disease but unfortunately despite encouraging advances a vaccine is not likely soon. DNA helicases from the PcrA/UvrD/Rep (PUR) subfamily are important for the survival of the various organisms, mainly pathogenic bacteria. Members from this subfamily can be targeted and inhibited by a variety of synthetic compounds. Using bioinformatics analysis we have shown that UvrD from this subfamily is the only member present in the P. falciparum genome, while PcrA and Rep are absent in the genome. UvrD from the parasite shows no homology to any protein or enzyme from human and thus can be considered as a strong potential drug target. In the present study we report an in silico analysis of this important enzyme from a variety of Plasmodium species. The results suggest that among all the species of Plasmodium, P. falciparum contains the largest UvrD and this enzyme is variable at the sequence and structural level. © 2013 Landes Bioscience. Source

Tuteja R.,Malaria Group
Parasitology International | Year: 2011

An interesting element of eukaryotic genomes is the large quantity of non-coding intervening sequences commonly known as introns, which regularly interrupt functional genes and therefore must be removed prior to the use of genetic information by the cell. After splicing, the mature RNA is exported from the nucleus to the cytoplasm. Any error in the process of recognition and removal of introns, or splicing, would lead to change in genetic message and thus has potentially catastrophic consequences. Thus splicing is a highly complex essential step in eukaryotic gene expression. It takes place in spliceosome, which is a dynamic RNA-protein complex made of snRNPs and non-snRNP proteins. The splicing process consists of following sequential steps: spliceosome formation, the first transesterification and second transesterification reactions, release of the mature mRNA and recycling of the snRNPs. The spliceosomal components produce a complex network of RNA-RNA, RNA-protein and protein-protein interactions and spliceosome experience remodeling during each splicing cycle. Helicases are essentially required at almost each step for resolution of RNA-RNA and/or RNA-protein interactions. RNA helicases share a highly conserved helicase domain which includes the motif DExD/H in the single letter amino acid code. This article will focus on members of the DExD/H-box proteins involved specially in splicing in the malaria parasite Plasmodium falciparum. © 2011 Elsevier Ireland Ltd. Source

Reddy K.S.,Malaria Group | Amlabu E.,Malaria Group | Pandey A.K.,Malaria Group | Mitra P.,Malaria Group | And 3 more authors.
Proceedings of the National Academy of Sciences of the United States of America | Year: 2015

Erythrocyte invasion by Plasmodium falciparum merozoites is a highly intricate process in which Plasmodium falciparum reticulocyte binding-like homologous protein 5 (PfRH5) is an indispensable parasite ligand that binds with its erythrocyte receptor, Basigin. PfRH5 is a leading blood-stage vaccine candidate because it exhibits limited polymorphisms and elicits potent strain-transcending parasite neutralizing antibodies. However, the mechanism by which it is anchored to the merozoite surface remains unknown because both PfRH5 and the PfRH5-interacting protein (PfRipr) lack transmembrane domains and GPI anchors. Here we have identified a conserved GPI-linked parasite protein, Cysteine-rich protective antigen (CyRPA) as an interacting partner of PfRH5-PfRipr that tethers the PfRH5/ PfRipr/CyRPAmultiprotein complex on the merozoite surface. CyRPA was demonstrated to be GPI-linked, localized in the micronemes, and essential for erythrocyte invasion. Specific antibodies against the three proteins successfully detected the intact complex in the parasite and coimmunoprecipitated the three interacting partners. Importantly, full-length CyRPA antibodies displayed potent straintranscending invasion inhibition, as observed for PfRH5. CyRPA does not bind with erythrocytes, suggesting that its parasite neutralizing antibodies likely block its critical interaction with PfRH5-PfRipr, leading to a blockade of erythrocyte invasion. Further, CyRPA and PfRH5 antibody combinations produced synergistic invasion inhibition, suggesting that simultaneous blockade of the PfRH5-Basigin and PfRH5/PfRipr/CyRPA interactions produced an enhanced inhibitory effect. Our discovery of the critical interactions between PfRH5, PfRipr, and the GPI-anchored CyRPA clearly defines the components of the essential PfRH5 adhesion complex for P. falciparum erythrocyte invasion and offers it as a previously unidentified potent target for antimalarial strategies that could abrogate formation of the crucial multiprotein complex. Source

Mehta J.,Malaria Group | Tuteja R.,Malaria Group
Molecular and Biochemical Parasitology | Year: 2011

Helicases are ubiquitous essential enzymes which have significant role in the nucleic acid metabolism. Using in silico approaches in the recent past we have identified a number of helicases in the Plasmodium falciparum genome. In the present study we report purification and detailed characterization of a novel helicase from P. falciparum. Our results indicate that this helicase is a homologue of Dbp5 and DDX19 from yeast and human, respectively. The biochemical characterization shows that it contains DNA and RNA unwinding, nucleic acid dependent ATPase and RNA binding activities. It is interesting to note that this enzyme can unwind DNA duplexes in both 5′ to 3′ and 3′ to 5′ directions. Using truncated derivatives we further show that Q motif is essentially required for all of its activities. These studies should make an important contribution in understanding the enzymes involved in nucleic acid metabolism in the parasite. © 2010 Elsevier B.V. All rights reserved. Source

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