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KMID : 1094720130180030491
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Biotechnology and Bioprocess Engineering
2013 Volume.18 No. 3 p.491 ~ p.500
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Drug target prediction using elementary mode analysis in Ascaris lumbricoides energy metabolism
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Parvatham K.
Veerakumari L.
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Abstract
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Ascariasis, an intestinal worm infection is caused by the parasite Ascaris lumbricoides and a report by World Health Organization (WHO) on soil transmitted helminths suggests that over one billion people are affected by Ascariasis. This disease is prevalent in developing countries, and in places of poor sanitation and unhygienic conditions. Even though anthelminthic drugs are available for the treatment of ascariasis, it is considered as a neglected tropical disease (NTD). Resistance of the parasite to the existing drugs necessitates a detailed study of its energy metabolism for identification of new drug targets. The catabolic pathway of the parasite is an evolved design well suited for parasitic life and obtains constant input from its host. Its energy metabolism is predominantly anaerobic. The parasite mitochondrion plays a key role as it lacks the functional tricarboxylic acid cycle (TCA cycle) and cytochrome oxidase activity. In adult ascarid mitochondrion, there is no external final electron acceptor and endogenously produced fumarate and 2-methyl branched-chain enoyl ? CoAs function as the terminal electron acceptors instead of oxygen. In this study, elementary flux mode analysis (EFM), a metabolic pathway analysis tool has been applied to model energy metabolism of the parasite A. lumbricoides. This study identifies a set of enzymes that have been suggested to be essential for the survival of the parasite; the inhibition of these enzymes paralyzes the parasite. The key enzymes of glycolysis and the phosphoenolpyruvate carboxykinase-succinate pathway are identified as drug targets since the knock-out of any of these enzymes results in zero flux value for all EFM that have been identified.
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KEYWORD
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Ascaris lumbricoides, carbohydrate catabolism, elementary flux mode, control effective flux, anaerobic mitochondria
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