scholarly journals CASTLE: A database of synthetic lethal sets predicted from genome-scale metabolic networks

2021 ◽  
Author(s):  
Vimaladhasan Senthamizhan ◽  
Sunanda Subramaniam ◽  
Arjun Raghavan ◽  
Karthik Raman
Keyword(s):  
Flux Balance Analysis ◽  
Efficient Algorithm ◽  
Drug Targets ◽  
Metabolic Networks ◽  
Synthetic Lethal ◽  
Flux Balance ◽  
Balance Analysis ◽  
Genome Scale ◽  
Synthetic Lethals ◽  
Novel Therapeutic

AbstractSummaryGenome-scale metabolic networks have been reconstructed for hundreds of organisms over the last two decades, with wide-ranging applications, including the identification of drug targets. Constraint-based approaches such as flux balance analysis have been effectively used to predict single and combinatorial drug targets in a variety of metabolic networks. We have previously developed Fast-SL, an efficient algorithm to rapidly enumerate all possible synthetic lethals from metabolic networks. Here, we introduce CASTLE, an online standalone database, which contains synthetic lethals predicted from the metabolic networks of over 130 organisms. These targets include single, double or triple lethal set of genes and reactions, and have been predicted using the Fast-SL algorithm. The workflow used for building CASTLE can be easily applied to other pathogenic models and used to identify novel therapeutic targets.AvailabilityCASTLE is available at https://ramanlab.github.io/CASTLE/[email protected]

scholarly journals Understanding the host-microbe interactions using metabolic modeling

Microbiome ◽  
2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Jack Jansma ◽  
Sahar El Aidy
Keyword(s):  
Human Health ◽  
Flux Balance Analysis ◽  
Bacterial Species ◽  
Flux Balance ◽  
Interaction Field ◽  
In Silico Simulation ◽  
Balance Analysis ◽  
Microbe Interactions ◽  
Host Microbe Interactions ◽  
Genome Scale

AbstractThe human gut harbors an enormous number of symbiotic microbes, which is vital for human health. However, interactions within the complex microbiota community and between the microbiota and its host are challenging to elucidate, limiting development in the treatment for a variety of diseases associated with microbiota dysbiosis. Using in silico simulation methods based on flux balance analysis, those interactions can be better investigated. Flux balance analysis uses an annotated genome-scale reconstruction of a metabolic network to determine the distribution of metabolic fluxes that represent the complete metabolism of a bacterium in a certain metabolic environment such as the gut. Simulation of a set of bacterial species in a shared metabolic environment can enable the study of the effect of numerous perturbations, such as dietary changes or addition of a probiotic species in a personalized manner. This review aims to introduce to experimental biologists the possible applications of flux balance analysis in the host-microbiota interaction field and discusses its potential use to improve human health.

scholarly journals Why does yeast ferment? A flux balance analysis study

2010 ◽  
Vol 38 (5) ◽  
pp. 1225-1229 ◽  
Author(s):  
Evangelos Simeonidis ◽  
Ettore Murabito ◽  
Kieran Smallbone ◽  
Hans V. Westerhoff
Keyword(s):  
Flux Balance Analysis ◽  
Energy Cost ◽  
Yeast Fermentation ◽  
Minimal Amount ◽  
Aerobic Growth ◽  
Analysis Study ◽  
Flux Balance ◽  
Balance Analysis ◽  
Genome Scale ◽  
Excess Glucose

Advances in biological techniques have led to the availability of genome-scale metabolic reconstructions for yeast. The size and complexity of such networks impose limits on what types of analyses one can perform. Constraint-based modelling overcomes some of these restrictions by using physicochemical constraints to describe the potential behaviour of an organism. FBA (flux balance analysis) highlights flux patterns through a network that serves to achieve a particular objective and requires a minimal amount of data to make quantitative inferences about network behaviour. Even though FBA is a powerful tool for system predictions, its general formulation sometimes results in unrealistic flux patterns. A typical example is fermentation in yeast: ethanol is produced during aerobic growth in excess glucose, but this pattern is not present in a typical FBA solution. In the present paper, we examine the issue of yeast fermentation against respiration during growth. We have studied a number of hypotheses from the modelling perspective, and novel formulations of the FBA approach have been tested. By making the observation that more respiration requires the synthesis of more mitochondria, an energy cost related to mitochondrial synthesis is added to the FBA formulation. Results, although still approximate, are closer to experimental observations than earlier FBA analyses, at least on the issue of fermentation.

Critical assessment of genome-scale metabolic models of Arabidopsis thaliana

2022 ◽  
Author(s):  
Javad Zamani ◽  
Sayed-Amir Marashi ◽  
Tahmineh Lohrasebi ◽  
Mohammad-Ali Malboobi ◽  
Esmail Foroozan
Keyword(s):  
Arabidopsis Thaliana ◽  
Flux Balance Analysis ◽  
Critical Assessment ◽  
Flux Balance ◽  
Balance Analysis ◽  
Metabolic Models ◽  
Living Organisms ◽  
Genome Scale

Genome-scale metabolic models (GSMMs) have enabled researchers to perform systems-level studies of living organisms. As a constraint-based technique, flux balance analysis (FBA) aids computation of reaction fluxes and prediction of...

scholarly journals Comparative Genome-Scale Metabolic Reconstruction and Flux Balance Analysis of Multiple Staphylococcus aureus Genomes Identify Novel Antimicrobial Drug Targets

2009 ◽  
Vol 191 (12) ◽  
pp. 4015-4024 ◽  
Author(s):  
Deok-Sun Lee ◽  
Henry Burd ◽  
Jiangxia Liu ◽  
Eivind Almaas ◽  
Olaf Wiest ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Flux Balance Analysis ◽  
In Silico ◽  
Drug Targets ◽  
Gene Deletion ◽  
Multidrug Resistant ◽  
Antimicrobial Drug ◽  
Metabolic Reconstruction ◽  
Flux Balance ◽  
Balance Analysis

ABSTRACT Mortality due to multidrug-resistant Staphylococcus aureus infection is predicted to surpass that of human immunodeficiency virus/AIDS in the United States. Despite the various treatment options for S. aureus infections, it remains a major hospital- and community-acquired opportunistic pathogen. With the emergence of multidrug-resistant S. aureus strains, there is an urgent need for the discovery of new antimicrobial drug targets in the organism. To this end, we reconstructed the metabolic networks of multidrug-resistant S. aureus strains using genome annotation, functional-pathway analysis, and comparative genomic approaches, followed by flux balance analysis-based in silico single and double gene deletion experiments. We identified 70 single enzymes and 54 pairs of enzymes whose corresponding metabolic reactions are predicted to be unconditionally essential for growth. Of these, 44 single enzymes and 10 enzyme pairs proved to be common to all 13 S. aureus strains, including many that had not been previously identified as being essential for growth by gene deletion experiments in S. aureus. We thus conclude that metabolic reconstruction and in silico analyses of multiple strains of the same bacterial species provide a novel approach for potential antibiotic target identification.

scholarly journals Simulating serial-target antibacterial drug synergies using flux balance analysis

2015 ◽  
Author(s):  
Andrew S Krueger ◽  
Christian Munck ◽  
Gautam Dantas ◽  
George M Church ◽  
James Galagan ◽  
...  
Keyword(s):  
Flux Balance Analysis ◽  
Enzyme Inhibitors ◽  
Metabolic Inhibitors ◽  
Metabolic Enzyme ◽  
Antibacterial Drug ◽  
Flux Balance ◽  
Single Target ◽  
Metabolic Systems ◽  
Balance Analysis ◽  
Genome Scale

Flux balance analysis (FBA) is an increasingly useful approach for modeling the behavior of metabolic systems. However, standard FBA modeling of genetic knockouts can not predict drug combination synergies observed between serial metabolic targets, even though such synergies give rise to some of the most widely used antibiotic treatments. Here we extend FBA modeling to simulate responses to chemical inhibitors at varying concentrations, by diverting enzymatic flux to a waste reaction. This flux diversion yields very similar qualitative predictions to prior methods for single target activity. However, we find very different predictions for combinations, where flux diversion, which mimics the kinetics of competitive metabolic inhibitors, can explain serial target synergies between metabolic enzyme inhibitors that we confirmed in Escherichia coli cultures. FBA flux diversion opens the possibility for more accurate genome-scale predictions of drug synergies, which can be used to suggest treatments for infections and other diseases.

scholarly journals Modeling the Differences in Biochemical Capabilities ofPseudomonasSpecies by Flux Balance Analysis: How Good Are Genome-Scale Metabolic Networks at Predicting the Differences?

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Parizad Babaei ◽  
Tahereh Ghasemi-Kahrizsangi ◽  
Sayed-Amir Marashi
Keyword(s):  
In Silico ◽  
Metabolic Networks ◽  
Closely Related Species ◽  
Systematic Analysis ◽  
Reconstruction Process ◽  
Flux Balance ◽  
Wide Range ◽  
Balance Analysis ◽  
Metabolic Models ◽  
Genome Scale

To date, several genome-scale metabolic networks have been reconstructed. These models cover a wide range of organisms, from bacteria to human. Such models have provided us with a framework for systematic analysis of metabolism. However, little effort has been put towards comparing biochemical capabilities of closely related species using their metabolic models. The accuracy of a model is highly dependent on the reconstruction process, as some errors may be included in the model during reconstruction. In this study, we investigated the ability of threePseudomonasmetabolic models to predict the biochemical differences, namely, iMO1086, iJP962, and iSB1139, which are related toP. aeruginosaPAO1,P. putidaKT2440, andP. fluorescensSBW25, respectively. We did a comprehensive literature search for previous works containing biochemically distinguishable traits over these species. Amongst more than 1700 articles, we chose a subset of them which included experimental results suitable forin silicosimulation. By simulating the conditions provided in the actual biological experiment, we performed case-dependent tests to compare thein silicoresults to the biological ones. We found out that iMO1086 and iJP962 were able to predict the experimental data and were much more accurate than iSB1139.

DYNAMIC FLUX BALANCE ANALYSIS FOR PREDICTING GENE OVEREXPRESSION EFFECTS IN BATCH CULTURES

2014 ◽  
Vol 22 (03) ◽  
pp. 327-338 ◽  
Author(s):  
CAROL MILENA BARRETO-RODRIGUEZ ◽  
JESSICA PAOLA RAMIREZ-ANGULO ◽  
JORGE MARIO GOMEZ RAMIREZ ◽  
LUKE ACHENIE ◽  
HAROLD MOLINA-BULLA ◽  
...  
Keyword(s):  
Flux Balance Analysis ◽  
Metabolic Networks ◽  
Ethanol Concentration ◽  
Batch Cultures ◽  
Dynamic Flux Balance Analysis ◽  
Optimization Framework ◽  
Flux Balance ◽  
Balance Analysis ◽  
Engineering Strategy ◽  
Technological Platforms

The advent of numerous technological platforms for genome sequencing has led to increasing understanding and construction of metabolic networks. A popular system engineering strategy is used to analyze microbial metabolic networks is flux balance analysis (FBA). In recent times, there has been a lot of interest in the study of the metabolic network dynamics when genes are overexpressed in the system. Herein, an optimization framework, which employs dynamic flux balance analysis (DFBA) is proposed for predicting ethanol concentration profiles in glycerol fermentations using Escherichia coli. In silico results were experimentally validated by overexpressing alcohol/acetaldehyde dehydrogenase adhE, pyruvate kinase pykF, pyruvate formate-lyase pflB and isoleucine-valine enzymes ilvC and llvL.

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