scholarly journals rMTA: robust metabolic transformation analysis

2019 ◽  
Vol 35 (21) ◽  
pp. 4350-4355
Author(s):  
Luis V Valcárcel ◽  
Verónica Torrano ◽  
Luis Tobalina ◽  
Arkaitz Carracedo ◽  
Francisco J Planes
Keyword(s):  
Drug Targets ◽  
Metabolic Networks ◽  
Gene Knockout ◽  
Supplementary Information ◽  
Case Scenario ◽  
Worst Case ◽  
Healthy State ◽  
Metabolic Transformation ◽  
Relevant Topic ◽  
Genome Scale

Abstract Motivation The development of computational tools exploiting -omics data and high-quality genome-scale metabolic networks for the identification of novel drug targets is a relevant topic in Systems Medicine. Metabolic Transformation Algorithm (MTA) is one of these tools, which aims to identify targets that transform a disease metabolic state back into a healthy state, with potential application in any disease where a clear metabolic alteration is observed. Results Here, we present a robust extension to MTA (rMTA), which additionally incorporates a worst-case scenario analysis and minimization of metabolic adjustment to evaluate the beneficial effect of gene knockouts. We show that rMTA complements MTA in the different datasets analyzed (gene knockout perturbations in different organisms, Alzheimer’s disease and prostate cancer), bringing a more accurate tool for predicting therapeutic targets. Availability and implementation rMTA is freely available on The Cobra Toolbox: https://opencobra.github.io/cobratoolbox/latest/. Supplementary information Supplementary data are available at Bioinformatics online.

scholarly journals Efficient reaction deletion algorithms for redesign of constraint-based metabolic networks for metabolite production with weak coupling

2019 ◽  
Author(s):  
Takeyuki Tamura
Keyword(s):  
Strong Coupling ◽  
Metabolic Networks ◽  
Search Space ◽  
Anaerobic Conditions ◽  
Case Scenario ◽  
Worst Case ◽  
Metabolic Network Analysis ◽  
Network Topologies ◽  
Genome Scale ◽  
Parameter Values

AbstractBackgroundMetabolic network analysis through flux balance is an established method for the computational redesign of production strains in metabolic engineering. The computational redesign is often based on reaction deletions from the original wild type networks. A key principle often used in this method is the production of target metabolites as by-products of cell growth. From a viewpoint of bioinformatics, it is very important to prepare a set of algorithms that can determine reaction deletions that achieve growth coupling whatever network topologies, target metabolites and parameter values will be considered in the future. Recently, the strong coupling-based method was used to demonstrate that the coupling of growth and production is possible for nearly all metabolites through reaction deletions in genome-scale metabolic models of Escherichia coli and Saccharomyces cerevisiae under aerobic conditions. However, when growing S. cerevisiae under anaerobic conditions, deletion strategies using the strong coupling-based method were possible for only 3.9% of all metabolites. Therefore, it is necessary to develop algorithms that can achieve growth coupling by reaction deletions for the conditions that the strong coupling-based method was not efficient.ResultsWe developed an algorithm that could calculate the reaction deletions that achieve the coupling of growth and production for 91.3% metabolites in genome-scale models of S. cerevisiae under anaerobic conditions. This analysis was conducted for the worst-case-scenario using flux variability analysis. To demonstrate the feasibility of the coupling, we derived appropriate reaction deletions using the new algorithm for target production in which the search space was divided into small cubes (CubeProd).ConclusionsWe developed a novel algorithm, CubeProd, to demonstrate that growth coupling is possible for most metabolites in S.cerevisiae under anaerobic conditions. This may imply that growth coupling is possible by reaction deletions for most target metabolites in any genome-scale constraint-based metabolic networks. The developed software, CubeProd, implemented in MATLAB, and the obtained reaction deletion strategies are freely available.

scholarly journals Efficient reaction deletion algorithms for redesign of constraint-based metabolic networks for metabolite production with weak coupling

2020 ◽  
Author(s):  
Takeyuki Tamura
Keyword(s):  
Strong Coupling ◽  
Metabolic Networks ◽  
Search Space ◽  
Anaerobic Conditions ◽  
Case Scenario ◽  
Worst Case ◽  
Metabolic Network Analysis ◽  
Network Topologies ◽  
Genome Scale ◽  
Parameter Values

Abstract Background: Metabolic network analysis through flux balance is an established method for the computational redesign of production strains in metabolic engineering. The computational redesign is often based on reaction deletions from the original wild type networks. A key principle often used in this method is the production of target metabolites as by-products of cell growth. From a viewpoint of bioinformatics, it is very important to prepare a set of algorithms that can determine reaction deletions that achieve growth coupling whatever network topologies, target metabolites and parameter values will be considered in the future. Recently, the strong coupling-based method was used to demonstrate that the coupling of growth and production is possible for nearly all metabolites through reaction deletions in genome-scale metabolic models of Escherichia coli and Saccharomyces cerevisiae under aerobic conditions. However, when growing S. cerevisiae under anaerobic conditions, deletion strategies using the strong coupling-based method were possible for only 3.9% of all metabolites. Therefore, it is necessary to develop algorithms that can achieve growth coupling by reaction deletions for the conditions that the strong coupling-based method was not efficient. Results: We developed an algorithm that could calculate the reaction deletions that achieve the coupling of growth and production for 91.3% metabolites in genome-scale models of S. cerevisiae under anaerobic conditions. This analysis was conducted for the worst-case scenario using flux variability analysis. To demonstrate the feasibility of the coupling, we derived appropriate reaction deletions using the new algorithm for target production in which the search space was divided into small cubes (CubeProd). Conclusions: We developed a novel algorithm, CubeProd, to demonstrate that growth coupling is possible for most metabolites in S.cerevisiae under anaerobic conditions. This may imply that growth coupling is possible by reaction deletions for most target metabolites in any genome-scale constraint-based metabolic networks. The developed software, CubeProd, implemented in MATLAB, and the obtained reaction deletion strategies are freely available.

scholarly journals Metabolic network-guided binning of metagenomic sequence fragments

2015 ◽  
Vol 32 (6) ◽  
pp. 867-874 ◽  
Author(s):  
Matthew B. Biggs ◽  
Jason A. Papin
Keyword(s):  
Metabolic Network ◽  
Dna Sequences ◽  
Metabolic Networks ◽  
Human Microbiome ◽  
Environmental Dna ◽  
Human Microbiome Project ◽  
Supplementary Information ◽  
Metagenomic Sequence ◽  
Connectivity Score ◽  
Genome Scale

Abstract Motivation: Most microbes on Earth have never been grown in a laboratory, and can only be studied through DNA sequences. Environmental DNA sequence samples are complex mixtures of fragments from many different species, often unknown. There is a pressing need for methods that can reliably reconstruct genomes from complex metagenomic samples in order to address questions in ecology, bioremediation, and human health. Results: We present the SOrting by NEtwork Completion (SONEC) approach for assigning reactions to incomplete metabolic networks based on a metabolite connectivity score. We successfully demonstrate proof of concept in a set of 100 genome-scale metabolic network reconstructions, and delineate the variables that impact reaction assignment accuracy. We further demonstrate the integration of SONEC with existing approaches (such as cross-sample scaffold abundance profile clustering) on a set of 94 metagenomic samples from the Human Microbiome Project. We show that not only does SONEC aid in reconstructing species-level genomes, but it also improves functional predictions made with the resulting metabolic networks. Availability and implementation: The datasets and code presented in this work are available at: https://bitbucket.org/mattbiggs/sorting_by_network_completion/. Contact: [email protected] Supplementary information: Supplementary data are available at Bioinformatics online.

scholarly journals FALCONET: an R package to accelerate automatic visualisation of genome scale metabolic models

2019 ◽  
Author(s):  
Hongzhong Lu ◽  
Zhengming Zhu ◽  
Eduard J Kerkhoven ◽  
Jens Nielsen
Keyword(s):  
Metabolic Networks ◽  
R Package ◽  
Network Size ◽  
Research Community ◽  
Supplementary Information ◽  
Large Network ◽  
Strain Design ◽  
Scale Models ◽  
Genome Scale ◽  
Integrative Omics

AbstractSummaryFALCONET (FAst visuaLisation of COmputational NETworks) enables the automatic for-mation and visualisation of metabolic maps from genome-scale models with R and CellDesigner, readily facilitating the visualisation of multi-layers omics datasets in the context of metabolic networks.MotivationUntil now, numerous GEMs have been reconstructed and used as scaffolds to conduct integrative omics analysis and in silico strain design. Due to the large network size of GEMs, it is challenging to produce and visualize these networks as metabolic maps for further in-depth analyses.ResultsHere, we presented the R package - FALCONET, which facilitates drawing and visualizing metabolic maps in an automatic manner. This package will benefit the research community by allowing a wider use of GEMs in systems biology.Availability and implementationFALCONET is available on https://github.com/SysBioChalmers/FALCONET and released under the MIT [email protected] informationSupplementary data are available online.

scholarly journals Boosting the extraction of elementary flux modes in genome-scale metabolic networks using the linear programming approach

2020 ◽  
Vol 36 (14) ◽  
pp. 4163-4170
Author(s):  
Francisco Guil ◽  
José F Hidalgo ◽  
José M García
Keyword(s):  
Linear Programming ◽  
Metabolic Networks ◽  
Supplementary Information ◽  
Programming Approach ◽  
Supplementary Data ◽  
Main Interest ◽  
Elementary Flux Modes ◽  
Order Of Magnitude ◽  
Genome Scale ◽  
Efficiency Rate

Abstract Motivation Elementary flux modes (EFMs) are a key tool for analyzing genome-scale metabolic networks, and several methods have been proposed to compute them. Among them, those based on solving linear programming (LP) problems are known to be very efficient if the main interest lies in computing large enough sets of EFMs. Results Here, we propose a new method called EFM-Ta that boosts the efficiency rate by analyzing the information provided by the LP solver. We base our method on a further study of the final tableau of the simplex method. By performing additional elementary steps and avoiding trivial solutions consisting of two cycles, we obtain many more EFMs for each LP problem posed, improving the efficiency rate of previously proposed methods by more than one order of magnitude. Availability and implementation Software is freely available at https://github.com/biogacop/Boost_LP_EFM. Contact [email protected] Supplementary information Supplementary data are available at Bioinformatics online.

scholarly journals Privacy-Preserving and Robust Watermarking on Sequential Genome Data using Belief Propagation and Local Differential Privacy

2021 ◽  
Author(s):  
Abdullah Çağlar Öksüz ◽  
Erman Ayday ◽  
Uğur Güdükbay
Keyword(s):  
Belief Propagation ◽  
Differential Privacy ◽  
Service Providers ◽  
Genome Project ◽  
Supplementary Information ◽  
Case Scenario ◽  
Worst Case ◽  
Collusion Attacks ◽  
Genome Data ◽  
The Impact

Abstract Motivation Genome data is a subject of study for both biology and computer science since the start of the Human Genome Project in 1990. Since then, genome sequencing for medical and social purposes becomes more and more available and affordable. Genome data can be shared on public websites or with service providers. However, this sharing compromises the privacy of donors even under partial sharing conditions. We mainly focus on the liability aspect ensued by the unauthorized sharing of these genome data. One of the techniques to address the liability issues in data sharing is the watermarking mechanism. Results To detect malicious correspondents and service providers (SPs) -whose aim is to share genome data without individuals’ consent and undetected-, we propose a novel watermarking method on sequential genome data using belief propagation algorithm. In our method, we have two criteria to satisfy. (i) Embedding robust watermarks so that the malicious adversaries can not temper the watermark by modification and are identified with high probability (ii) Achieving ε-local differential privacy in all data sharings with SPs. For the preservation of system robustness against single SP and collusion attacks, we consider publicly available genomic information like Minor Allele Frequency, Linkage Disequilibrium, Phenotype Information and Familial Information. Our proposed scheme achieves 100% detection rate against the single SP attacks with only 3% watermark length. For the worst case scenario of collusion attacks (50% of SPs are malicious), 80% detection is achieved with 5% watermark length and 90% detection is achieved with 10% watermark length. For all cases, the impact of ε on precision remained negligible and high privacy is ensured. Availability https://github.com/acoksuz/PPRW_SGD_BPLDP Supplementary information Supplementary data are available at Bioinformatics online.

scholarly journals MinReact: a systematic approach for identifying minimal metabolic networks

2020 ◽  
Vol 36 (15) ◽  
pp. 4309-4315
Author(s):  
Gayathri Sambamoorthy ◽  
Karthik Raman
Keyword(s):  
Network Structure ◽  
Metabolic Networks ◽  
Systematic Approach ◽  
Supplementary Information ◽  
Supplementary Data ◽  
Original Network ◽  
Compensatory Reactions ◽  
Genome Scale ◽  
Minimal Networks

Abstract Motivation Genome-scale metabolic models are widely constructed and studied for understanding various design principles underlying metabolism, predominantly redundancy. Metabolic networks are highly redundant and it is possible to minimize the metabolic networks into smaller networks that retain the functionality of the original network. Results Here, we establish a new method, MinReact that systematically removes reactions from a given network to identify minimal reactome(s). We show that our method identifies smaller minimal reactomes than existing methods and also scales well to larger metabolic networks. Notably, our method exploits known aspects of network structure and redundancy to identify multiple minimal metabolic networks. We illustrate the utility of MinReact by identifying multiple minimal networks for 77 organisms from the BiGG database. We show that these multiple minimal reactomes arise due to the presence of compensatory reactions/pathways. We further employed MinReact for a case study to identify the minimal reactomes of different organisms in both glucose and xylose minimal environments. Identification of minimal reactomes of these different organisms elucidate that they exhibit varying levels of redundancy. A comparison of the minimal reactomes on glucose and xylose illustrates that the differences in the reactions required to sustain growth on either medium. Overall, our algorithm provides a rapid and reliable way to identify minimal subsets of reactions that are essential for survival, in a systematic manner. Availability and implementation Algorithm is available from https://github.com/RamanLab/MinReact. Supplementary information Supplementary data are available at Bioinformatics online.

scholarly journals Exploring gene knockout strategies to identify potential drug targets using genome-scale metabolic models

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Abhijit Paul ◽  
Rajat Anand ◽  
Sonali Porey Karmakar ◽  
Surender Rawat ◽  
Nandadulal Bairagi ◽  
...  
Keyword(s):  
Cell Lines ◽  
Drug Targets ◽  
Gene Knockout ◽  
Single Gene ◽  
Potential Drug ◽  
Growth Reduction ◽  
Gene Ranking ◽  
Metabolic Models ◽  
Genome Scale ◽  
Potential Drug Targets

AbstractResearch on new cancer drugs is performed either through gene knockout studies or phenotypic screening of drugs in cancer cell-lines. Both of these approaches are costly and time-consuming. Computational framework, e.g., genome-scale metabolic models (GSMMs), could be a good alternative to find potential drug targets. The present study aims to investigate the applicability of gene knockout strategies to be used as the finding of drug targets using GSMMs. We performed single-gene knockout studies on existing GSMMs of the NCI-60 cell-lines obtained from 9 tissue types. The metabolic genes responsible for the growth of cancerous cells were identified and then ranked based on their cellular growth reduction. The possible growth reduction mechanisms, which matches with the gene knockout results, were described. Gene ranking was used to identify potential drug targets, which reduce the growth rate of cancer cells but not of the normal cells. The gene ranking results were also compared with existing shRNA screening data. The rank-correlation results for most of the cell-lines were not satisfactory for a single-gene knockout, but it played a significant role in deciding the activity of drug against cell proliferation, whereas multiple gene knockout analysis gave better correlation results. We validated our theoretical results experimentally and showed that the drugs mitotane and myxothiazol can inhibit the growth of at least four cell-lines of NCI-60 database.

scholarly journals Modeling the metabolic interplay between a parasitic worm and its bacterial endosymbiont allows the identification of novel drug targets

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
David M Curran ◽  
Alexandra Grote ◽  
Nirvana Nursimulu ◽  
Adam Geber ◽  
Dennis Voronin ◽  
...  
Keyword(s):  
Drug Targets ◽  
Metabolic Networks ◽  
Metabolic Model ◽  
Endosymbiotic Bacteria ◽  
Parasitic Worm ◽  
Eukaryotic Organisms ◽  
New Treatments ◽  
Genome Scale ◽  
Novel Drug ◽  
Novel Drug Targets

The filarial nematode Brugia malayi represents a leading cause of disability in the developing world, causing lymphatic filariasis in nearly 40 million people. Currently available drugs are not well-suited to mass drug administration efforts, so new treatments are urgently required. One potential vulnerability is the endosymbiotic bacteria Wolbachia—present in many filariae—which is vital to the worm. Genome scale metabolic networks have been used to study prokaryotes and protists and have proven valuable in identifying therapeutic targets, but have only been applied to multicellular eukaryotic organisms more recently. Here, we present iDC625, the first compartmentalized metabolic model of a parasitic worm. We used this model to show how metabolic pathway usage allows the worm to adapt to different environments, and predict a set of 102 reactions essential to the survival of B. malayi. We validated three of those reactions with drug tests and demonstrated novel antifilarial properties for all three compounds.

scholarly journals SAMMI: a semi-automated tool for the visualization of metabolic networks

2019 ◽  
Vol 36 (8) ◽  
pp. 2616-2617
Author(s):  
Andre Schultz ◽  
Rehan Akbani
Keyword(s):  
Large Scale ◽  
Metabolic Networks ◽  
Source Code ◽  
Supplementary Information ◽  
Network Partitioning ◽  
Web Based ◽  
Constraint Based Modeling ◽  
Context Specific ◽  
Genome Scale ◽  
Automated Tool

Abstract Summary Here we present a browser-based Semi-Automated Metabolic Map Illustrator (SAMMI) for the visualization of metabolic networks. While automated features allow for easy network partitioning, navigation, and node positioning, SAMMI also offers a wide array of manual map editing features. This combination allows for fast, context-specific visualization of metabolic networks as well as the development of standardized, large-scale, visually appealing maps. The implementation of SAMMI with popular constraint-based modeling toolboxes also allows for effortless visualization of simulation results of genome-scale metabolic models. Availability and implementation SAMMI has been implemented as a standalone web-based tool and as plug-ins for the COBRA and COBRApy toolboxes. SAMMI and its COBRA plugins are available under the GPL 3.0 license and are available along with documentation, tutorials, and source code at www.SammiTool.com. Supplementary information Supplementary data are available at Bioinformatics online.

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