In silico analysis of<i>Plasmodium</i>species specific UvrD helicase

Tuteja, Renu

doi:10.4161/cib.23125

Cited by 9 publications

(6 citation statements)

References 26 publications

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“…The in silico analysis of amino acid sequence of PfUvrD helicase revealed that it contains characteristic UvrD motifs ( Figure 6B ). Previously we have reported that all the Plasmodium species contain UvrD and P. falciparum contains the largest UvrD and this enzyme is significantly variable at the sequence and structural level among all the species of Plasmodium ( Tuteja, 2013 ). In previous studies we have reported that PfUvrD contains DNA helicase and ssDNA-dependent ATPase activities ( Ahmad et al, 2012 ).…”

Section: Resultsmentioning

confidence: 99%

Genome Wide In silico Analysis of the Mismatch Repair Components of Plasmodium falciparum and Their Comparison with Human Host

et al. 2017

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Malaria a major parasitic infection globally particularly in tropical and sub-tropical regions of the world is responsible for about 198 million cases and estimated deaths due to this disease are about 0.6 million. The emergence of drug resistance in the malaria parasite is alarming and it is necessary to understand its underlying cause and molecular mechanisms. It has been established that drug resistant malaria parasites have defective mismatch repair (MMR) therefore it is essential to study this pathway and its components in detail. Recently a number of non-synonymous Single Nucleotide Polymorphisms have been reported in genes involved in MMR pathways. PfMLH is an endonuclease essential to restore the MMR in drug resistant strains of Plasmodium falciparum. Considering all these facts about the role of MMR in emergence of drug resistant parasite, in this manuscript we report a genome wide analysis of the components of the MMR pathway such as MLH, Pms1, MSH2-1, MSH2-2, MSH6, and UvrD using in silico bioinformatics based approaches. The phylogenetic analysis revealed evolutionary closeness with the MMR components of various organisms. It is noteworthy that P. falciparum contains two homologs of MSH2, which are located on different chromosomes. The structural modeling of these components showed their similarity with the human/yeast MMR components. The docking studies reveal that PfUvrD and PfMLH interact with each other. The in silico identification of interacting partners of the major MMR components identified numerous P. falciparum specific proteins. In line with our previous studies the present study will also contribute significantly to understand the MMR pathway of malaria parasite.

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Section: Resultsmentioning

confidence: 99%

Genome Wide In silico Analysis of the Mismatch Repair Components of Plasmodium falciparum and Their Comparison with Human Host

et al. 2017

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“…UvrD is a member of superfamily one and is essential for the NER and mismatch repair (MMR) to repair mismatches occurring as a result of DNA damage or during DNA replication . Remarkably, P. falciparum and other Plasmodium species contain UvrD helicase but its homolog is absent in the human host . PfUvrD is a 1441 amino acid protein of ~ 170 kDa, and its various fragments have been biochemically characterized.…”

Section: Parasite‐specific Helicase Uvrdmentioning

confidence: 99%

Unraveling the importance of the malaria parasite helicases

Tuteja

2017

The FEBS Journal

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Malaria is a human parasitic disease caused by infection from Plasmodium species, particularly Plasmodium falciparum. Each year millions of people are infected with malaria and large numbers of deaths result due to this deadly infection. P. falciparum contains 14 chromosomes, nearly 5400 genes and a multistage life cycle in humans and mosquitoes. The control of malaria is still a challenge as the parasite is continuously developing resistance to available antimalarial drugs and the mosquito vector is developing resistance to insecticides. The availability of P. falciparum genome has resulted in the identification of parasite‐specific proteins that can be targeted without harmful effects to the human host. Toward this goal, we have been working on the identification and characterization of helicases in order to find parasite‐specific helicases, which can be used as novel drug targets to tackle the rising problem of drug resistance. Helicases are ATP‐dependent nucleic acid unwinding enzymes. The P. falciparum genome analysis depicts that it contains some parasite‐specific helicases and homologs to most of the human helicases. Here, we present an overview of P. falciparum helicases and their importance in parasite growth and survival.

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“…Although many putative therapeutic targets for malaria have been reported in the recent past [ 10 - 19 ] but further studies are required in order to get the insight for the successful development of suitable drugs. Helicases have also been proposed as suitable drug targets for human cancers as well as many pathogens including viruses and P. falciparum [ 20 - 33 ].…”

Section: Introductionmentioning

confidence: 99%

“…In particular, UvrD is required for the mismatch repair (MMR) and nucleotide excision repair (NER) to repair mismatches occurring during replication or DNA lesions such as UV-induced pyrimidine dimers or more bulky adducts [ 35 , 39 , 40 ]. In a recent study we have reported the detailed biochemical characterization of the UvrD helicase from P. falciparum and have shown that it exhibits the ssDNA-dependent ATPase activity and the DNA helicase activity in 3’ to 5’ direction [ 32 , 33 , 35 ]. Recent study on UvrD in different Plasmodium species revealed that the other species of Plasmodium also contain putative UvrD helicase [ 33 ].…”

Section: Introductionmentioning

confidence: 99%

“…In a recent study we have reported the detailed biochemical characterization of the UvrD helicase from P. falciparum and have shown that it exhibits the ssDNA-dependent ATPase activity and the DNA helicase activity in 3’ to 5’ direction [ 32 , 33 , 35 ]. Recent study on UvrD in different Plasmodium species revealed that the other species of Plasmodium also contain putative UvrD helicase [ 33 ].…”

Section: Introductionmentioning

confidence: 99%

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Plasmodium falciparum UvrD activities are downregulated by DNA-interacting compounds and its dsRNA inhibits malaria parasite growth

et al. 2014

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BackgroundHuman malaria parasite infection and its control is a global challenge which is responsible for ~0.65 million deaths every year globally. The emergence of drug resistant malaria parasite is another challenge to fight with malaria. Enormous efforts are being made to identify suitable drug targets in order to develop newer classes of drug. Helicases play crucial roles in DNA metabolism and have been proposed as therapeutic targets for cancer therapy as well as viral and parasitic infections. Genome wide analysis revealed that Plasmodium falciparum possesses UvrD helicase, which is absent in the human host.ResultsRecently the biochemical characterization of P. falciparum UvrD helicase revealed that N-terminal UvrD (PfUDN) hydrolyses ATP, translocates in 3’ to 5’ direction and interacts with MLH to modulate each other’s activity. In this follow up study, further characterization of P. falciparum UvrD helicase is presented. Here, we screened the effect of various DNA interacting compounds on the ATPase and helicase activity of PfUDN. This study resulted into the identification of daunorubicin (daunomycin), netropsin, nogalamycin, and ethidium bromide as the potential inhibitor molecules for the biochemical activities of PfUDN with IC50 values ranging from ~3.0 to ~5.0 μM. Interestingly etoposide did not inhibit the ATPase activity but considerable inhibition of unwinding activity was observed at 20 μM. Further study for analyzing the importance of PfUvrD enzyme in parasite growth revealed that PfUvrD is crucial/important for its growth ex-vivo.ConclusionsAs PfUvrD is absent in human hence on the basis of this study we propose PfUvrD as suitable drug target to control malaria. Some of the PfUvrD inhibitors identified in the present study can be utilized to further design novel and specific inhibitor molecules.

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In silico analysis ofPlasmodiumspecies specific UvrD helicase

Cited by 9 publications

References 26 publications

Genome Wide In silico Analysis of the Mismatch Repair Components of Plasmodium falciparum and Their Comparison with Human Host

Genome Wide In silico Analysis of the Mismatch Repair Components of Plasmodium falciparum and Their Comparison with Human Host

Unraveling the importance of the malaria parasite helicases

Plasmodium falciparum UvrD activities are downregulated by DNA-interacting compounds and its dsRNA inhibits malaria parasite growth

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