Exploring novel drug targets in fatty acid pathway of Plasmodium falciparum
TL;DR: This study explored and analyzed fatty acid biosynthesis occurring in the apicoplast using stoichiometric matrix, elementary flux modes and robustness analysis and found that a combinatorial double knock out of these enzymes predicts further reduction in overall pathway enzyme activity.
Abstract: Article history: Received on: 21/07/2015 Revised on: 20/08/2015 Accepted on: 13/09/2015 Available online: 28/10/2015 The malarial parasite Plasmodium falciparum infects humans and proliferates rapidly inside the host before its detection. The proliferation step requires a large amount of lipids for membrane synthesis. Thus fatty acid biosynthesis occurring in the apicoplast plays an important role in causing cerebral malaria. In this study, we explored and analyzed these pathways using stoichiometric matrix, elementary flux modes and robustness analysis. Based on the above analysis, the robustness of this pathway diminished as the result of virtual enzyme knock out indicating four key enzymes, 3-oxoacyl-ACP synthase, 3-oxoacyl-ACP synthase, 3-oxoacyl-ACP synthase and Glycerol-3-phosphate o-acyl transferase. Among the four, the first three are existing drug targets. Subsequently, we also found that a combinatorial double knock out of these enzymes predicts further reduction in overall pathway enzyme activity. Thus, we propose multi drug targeting as a better way to treat brain malaria.
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TL;DR: In this article, the authors present a flux balance analysis, a mathematical modeling approach often utilized by metabolic engineers to quantitatively simulate microbial metabolism, and apply it to the complete genome sequence for a number of organisms.
807 citations
"Exploring novel drug targets in fat..." refers methods in this paper
...It uses flux balance analysis (Kauffman et al., 2003), stoichiometric analysis and the reversibility status of the reactions involved to analyze the pathway....
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01 Mar 1999
TL;DR: Algorithms for computing the convex basis and elementary modes developed earlier are briefly reviewed, and a newly developed algorithm for detecting all enzyme subsets in a given network is presented.
Abstract: Motivation: To reconstruct metabolic pathways from biochemical and/or genome sequence data, the stoichiometric and thermodynamic feasibility of the pathways has to be tested. This is achieved by characterizing the admissible region of flux distributions in steady state. This region is spanned by what can be called a convex basis. The concept of 'elementary flux modes' provides a mathematical tool to define all metabolic routes that are feasible in a given metabolic network. In addition, we define 'enzyme subsets' to be groups of enzymes that operate together in fixed flux proportions in all steady states of the system. Results: Algorithms for computing the convex basis and elementary modes developed earlier are briefly reviewed. A newly developed algorithm for detecting all enzyme subsets in a given network is presented. All of these algorithms have been implemented in a novel computer program named METATOOL, whose features are outlined here. The algorithms are illustrated by an example taken from sugar metabolism. Availability: METATOOL is available from ftp://bmsdarwin.brookes.ac.uk/pub/software/ibmpc/metatool. Supplementary information: http://www.biologie.hu-berlin.de/biophysics/Theory/tpfeiffer/metatool.html.
388 citations
"Exploring novel drug targets in fat..." refers methods in this paper
...METATOOL is a novel computer program in which algorithms for calculating convex basis, stoichiometric matrix and enzyme subsets are implemented (Pfeiffer et al., 1999)....
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TL;DR: Network-based pathways are emerging as an important paradigm for analysis of biological systems, and can be described by simple descriptions of individual components such as product yield, network robustness, correlated reactions and predictions of minimal media.
354 citations
"Exploring novel drug targets in fat..." refers background in this paper
...This study has become relatively easier since the genomic era (Papin et al., 2003)....
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TL;DR: In an attempt to decipher the role of the organelle within the parasite, a closer look is taken at the transporters decorating the plastid to better understand the metabolic exchanges between the apicoplast and the rest of the parasite cell.
Abstract: The malaria parasite, Plasmodium falciparum, harbours a relict plastid known as the 'apicoplast'. The discovery of the apicoplast ushered in an exciting new prospect for drug development against the parasite. The eubacterial ancestry of the organelle offers a wealth of opportunities for the development of therapeutic interventions. Morphological, biochemical and bioinformatic studies of the apicoplast have further reinforced its 'plant-like' characteristics and potential as a drug target. However, we are still not sure why the apicoplast is essential for the parasite's survival. This review explores the origins and metabolic functions of the apicoplast. In an attempt to decipher the role of the organelle within the parasite we also take a closer look at the transporters decorating the plastid to better understand the metabolic exchanges between the apicoplast and the rest of the parasite cell.
313 citations
"Exploring novel drug targets in fat..." refers background in this paper
...An important feature of the apicoplast is that it interacts with the environment to import and export many molecules (Lim and McFadden, 2010)....
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TL;DR: What is known about the molecular and cellular basis of the developmental progression of parasites and their interactions with host tissues in the mosquito and during the early phase of mammalian infection is discussed.
Abstract: Plasmodium sporozoites are the product of a complex developmental process in the mosquito vector and are destined to infect the mammalian liver. Attention has been drawn to the mosquito stages and pre-erythrocytic stages owing to recognition that these are bottlenecks in the parasite life cycle and that intervention at these stages can block transmission and prevent infection. Parasite progression in the Anopheles mosquito, sporozoite transmission to the mammalian host by mosquito bite, and subsequent infection of the liver are characterized by extensive migration of invasive stages, cell invasion, and developmental changes. Preparation for the liver phase in the mammalian host begins in the mosquito with an extensive reprogramming of the sporozoite to support efficient infection and survival. Here, we discuss what is known about the molecular and cellular basis of the developmental progression of parasites and their interactions with host tissues in the mosquito and during the early phase of mammalian infection.
307 citations
"Exploring novel drug targets in fat..." refers background in this paper
...complicated life cycle, requiring both a human and a mosquito host, and differentiating multiple times during the transmission process (Aly et al., 2009)....
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...These malaria parasites have a complicated life cycle, requiring both a human and a mosquito host, and differentiating multiple times during the transmission process (Aly et al., 2009)....
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