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

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.

Plasmodium falciparum specific helicase 2 is a dual, bipolar helicase and is crucial for parasite growth

“…Therefore, it is very important to characterize these helicases and establish their role. Previously detailed biochemical characterization of PfUvrD and PfPSH3 has been reported and both these helicases are specific to parasite and are absent from the human host 35,37 . In this manuscript we have reported the detailed biochemical characterization of PfPSH2, a helicase that is specific to Plasmodium species.…”

“…PfUvrD is an important component of mismatch repair complex of P . falciparum 35 . PfUvrD is a DNA helicase and unwinds DNA duplex in 3′ to 5′ direction and it colocalizes and interacts with PfMLH, which modulates its unwinding activity.…”

Plasmodium falciparum Apn1 homolog is a mitochondrial base excision repair protein with restricted enzymatic functions

“…The other nuclear‐encoded Flap endonuclease lacks an N‐terminal organelle‐targeting element and is likely to be nuclear . For MMR, the single MutL homolog in P. falciparum is nuclear and three of its four MutS homologs (MSH2‐1, MSH2‐2, MSH6) are likely to mediate MMR in the nucleus as they lack organellar targeting elements . Thus, the apicoplast/mitochondrion might use a reduced or altered MMR pathway with the putative MutS functioning in conjunction with 5′–3′ and 3′–5′ exonucleases to remove mismatched bases.…”

Biochemical characterization of Plasmodium falciparum parasite specific helicase 1 (PfPSH1)

“…These findings suggest that helicases are crucial proteins and their characterization is important to understand the biological functions . Previously, we have reported the biochemical and functional characterization of few PSH such as PfUvrD, PfPSH3, and PfPSH2, which are not present in the human host .…”