Screening of potential targets in Plasmodium falciparum using stage-specific metabolic network analysis

Abstract

The Apicomplexa parasite Plasmodium is a major cause of death in developing countries which are less equipped to bring new medicines to the market. Currently available drugs used for treatment of malaria are limited either by inadequate efficacy, toxicity and/or increased resistance. Availability of the genome sequence, microarray data and metabolic profile of Plasmodium parasite offers an opportunity for the identification of stage-specific genes important to the organism's lifecycle. In this study, microarray data were analysed for differential expression and overlapped onto metabolic pathways to identify differentially regulated pathways essential for transition to successive erythrocytic stages. The results obtained indicate that S-adenosylmethionine decarboxylase/ornithine decarboxylase, a bifunctional enzyme required for polyamine synthesis, is important for the Plasmodium cell growth in the absence of exogenous polyamines. S-adenosylmethionine decarboxylase/ornithine decarboxylase is a valuable target for designing therapeutically useful inhibitors. One such inhibitor, [Formula: see text]-difluoromethyl ornithine, is currently in use for the treatment of African sleeping sickness caused by Trypanosoma brucei. Structural studies of ornithine decarboxylase along with known inhibitors and their analogues were carried out to screen drug databases for more effective and less toxic compounds.

Identifying Antimalarial Drug Targets by Cellular Network Analysis

“…FBA has been widely used to predict essential genes of the human malaria parasite P. falciparum [9,36,38]. A metabolic network reconstruction of P. falciparum was developed with 1001 reactions and 616 metabolites [36].…”

“…Several modifications on the linear programming implementation were studied to make the static FBA model more realistic. For example, gene expression profiles of the malaria parasite were integrated into metabolic models [9,36,38]. In the study of Plata et al [36], the maximum flux of the associated reactions was constrained by their expression level while Huthmacher et al [9] used a method proposed by Shlomi et al [39].…”

In Silico Knockout Screening of Plasmodium falciparum Reactions and Prediction of Novel Essential Reactions by Analysing the Metabolic Network

“…Flux balance analysis (FBA) is an in silico method used in gaining deepened understanding into the abilities and the metabolic behaviour of a cell [ 5 , 42 , 43 ]. It is an extensively used and deep-rooted method to assess the essential genes of a particular organism.…”

“…FBA is used extensively in the study of reconstructing the metabolic network of a genome based on mass conservation. Flux balance analysis envisages the complete growth rate of a particular organism or rate of utilization of any particular metabolite by simply calculating how the metabolites flow through the metabolic network [ 43 ]. The stoichiometry information of the metabolic network along with the metabolic target functions essential to the cell of interest is also necessitated by FBA [ 5 , 43 ].…”

Antimalarials with Benzothiophene Moieties as Aminoquinoline Partners

“…As artemisinin resistance has spread, posing a threat to malaria control [ 3 ], in order to prevent progression to life-threatening malaria artemisinin-based combination therapies (ACTs) have been recommended by the WHO [ 4 ]. A vaccine has yet to be discovered [ 5 ] and taking into account the constant loss of therapeutic efficacy due to the drug resistant strains, there is an urgent need for the discovery of new targets and treatments for malaria. Widespread chloroquine (CQ) resistance is largely attributable to mutations in the vacuole transmembrane protein (PfCRT) protein [ 6 , 7 ], found in the membrane of the digestive vacuole where hemoglobin digestion takes place.…”