Abstract
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.
Highlights
Human malaria is caused by different species of Plasmodium, an obligate intracellular parasite which requires two hosts to complete its life cycle, i.e., arthropod vector for sexual life cycle and human host for asexual life cycle (Tuteja, 2007, 2010; Ahmad and Tuteja, 2014)
We have reported the in silico analysis of all the major components of mismatch repair (MMR) machinery of malaria parasite P. falciparum and their comparative analysis with the components of the MMR pathway of human host and/or yeast
There are some differences in the major MMR components such as MSH3 is lacking in the parasite whereas UvrD is not present in the human host
Summary
Human malaria is caused by different species of Plasmodium, an obligate intracellular parasite which requires two hosts to complete its life cycle, i.e., arthropod vector for sexual life cycle and human host for asexual life cycle (liver and blood stages) (Tuteja, 2007, 2010; Ahmad and Tuteja, 2014). Analysis of the Mismatch Repair Components of Plasmodium falciparum in the tropical and subtropical regions of the developing world in rural regions. Plasmodium falciparum is prone to immune evasion that is due to the antigenic variation contributed by the multicopy var gene family. P. falciparum erythrocyte membrane protein 1 (PfEMP1), encoded by this multicopy var gene family expressed on the surface of infected red blood cells, plays an important role in this immune evasion. It has been reported that defective mismatch repair (MMR) pathway is responsible for drug resistance in malaria parasite (Castellini et al, 2011) MMR proteins of malaria parasite have gained attention for their characterization and role in drug resistance. It has been reported that human malaria parasite has unusual MMR pathway as compared to other eukaryotes (Bethke et al, 2007; Ahmad and Tuteja, 2014)
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