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A Method to Constrain Genome-Scale Models with 13C Labeling Data

Héctor García Martín, Vinay Satish Kumar, Daniel Weaver, Amit Ghosh, Victor Chubukov, Aindrila Mukhopadhyay, Adam Arkin, Jay D. Keasling, Costas D. Maranas
2015 PLoS Computational Biology  
The data from 13 OPEN ACCESS Citation: García Martín H, Kumar VS, Weaver D, Ghosh A, Chubukov V, Mukhopadhyay A, et al. (2015) A Method to Constrain Genome-Scale Models with 13 C Labeling Data.  ...  Here, we present a new method for calculating metabolic fluxes, key targets in metabolic engineering, that incorporates data from 13 C labeling experiments and genome-scale models.  ...  Hence, the method is robust with respect to experiment accuracy in 13 C labeling. doi:10.1371/journal.pcbi.1004363.g007 Constraining Genome-Scale Models with 13C Labeling Data PLOS Computational Biology  ... 
doi:10.1371/journal.pcbi.1004363 pmid:26379153 pmcid:PMC4574858 fatcat:s3zsay4drjbfhhuyne335uzawi

Achieving Metabolic Flux Analysis for S. cerevisiae at a Genome-Scale: Challenges, Requirements, and Considerations

Saratram Gopalakrishnan, Costas Maranas
2015 Metabolites  
Recent advances in 13C-Metabolic flux analysis (13C-MFA) have increased its capability to accurately resolve fluxes using a genome-scale model with narrow confidence intervals without pre-judging the activity  ...  This review aims to establish the necessary guidelines for performing 13C-MFA at the genome-scale for a compartmentalized eukaryotic system such as yeast in terms of model and data requirements, while  ...  Requirements for Genome-Scale MFA The primary requirements for performing MFA at the genome-scale are the availability of a well curated GSM model for S. cerevisiae, atom mapping data for every reaction  ... 
doi:10.3390/metabo5030521 pmid:26393660 pmcid:PMC4588810 fatcat:fogpc34hqbbuhl4gy7sbw5gjom

Studying metabolic flux adaptations in cancer through integrated experimental-computational approaches

Shoval Lagziel, Won Dong Lee, Tomer Shlomi
2019 BMC Biology  
Here, we review two widely used computational flux inference approaches: isotope tracing coupled with Metabolic Flux Analysis (13C-MFA) and COnstraint-Based Reconstruction and Analysis (COBRA).  ...  We describe the applications of these complementary modeling techniques for studying metabolic adaptations in cancer cells due to genetic mutations and the tumor microenvironment, as well as for identifying  ...  Further work is required to make such genome-scale 13C-MFA methods more accessible for the research community.  ... 
doi:10.1186/s12915-019-0669-x pmid:31272436 pmcid:PMC6609376 fatcat:twnkzsa66na6figuz5jbkqeo5y

13C metabolic flux analysis at a genome-scale

Saratram Gopalakrishnan, Costas D. Maranas
2015 Metabolic Engineering  
This study addresses the impact on prediction fidelity of scaling-up mapping models to a genome-scale.  ...  Stepping up to a genome-scale mapping model leads to wider flux inference ranges for 20 key reactions present in the core model.  ...  Successful 13C-MFA at a genome-scale requires a reliable GSM model along with detailed atom maps of every reaction in the network.  ... 
doi:10.1016/j.ymben.2015.08.006 pmid:26358840 fatcat:7zaoluvjerd77ndpj7k4gr2lw4

Constraining Genome-Scale Models to Represent the Bow Tie Structure of Metabolism for 13C Metabolic Flux Analysis

Tyler Backman, David Ando, Jahnavi Singh, Jay Keasling, Héctor García Martín
2018 Metabolites  
Constraining genome-scale models to represent the bow tie structure of metabolism for 13C metabolic flux analysis. Metabolites, 8 (1), [3] .  ...  The validity of this "two-scale" or "bow tie" approximation is supported both by the ability to accurately model experimental isotopic labeling data, and by experimentally verified metabolic engineering  ...  fluxes constrained by 13 C data for genome-scale models [23].  ... 
doi:10.3390/metabo8010003 pmid:29300340 pmcid:PMC5875993 fatcat:5px4uuulmrez7mnqhlnkbg73ve

Advances in metabolic flux analysis toward genome-scale profiling of higher organisms

Georg Basler, Alisdair R. Fernie, Zoran Nikoloski
2018 Bioscience Reports  
We provide an opinion of how recent local flux profiling approaches can be used in conjunction with the constraint-based modeling framework to arrive at genome-scale flux maps.  ...  However, in comparison with omics technologies, flux profiling has yet to provide comprehensive differential flux maps at a genome-scale and in different cell types, tissues, and organs.  ...  Competing Interests The authors declare that there are no competing interests associated with the manuscript.  ... 
doi:10.1042/bsr20170224 fatcat:ekblt65h4zhqdcmlbtzfc6e27e

Estimating Metabolic Fluxes Using a Maximum Network Flexibility Paradigm

Wout Megchelenbrink, Sergio Rossell, Martijn A. Huynen, Richard A. Notebaart, Elena Marchiori, Mukund Thattai
2015 PLoS ONE  
By mapping measured flux data from central metabolism to the genome-scale models of Escherichia coli and Saccharomyces cerevisiae we show that i) indeed, most of the measured fluxes agree with a high adaptability  ...  Motivation Genome-scale metabolic networks can be modeled in a constraint-based fashion.  ...  Our method can also be used on networks that are made tissue-or environment specific with computational methods that integrate omics data with genome-scale networks, such as iMAT [25] , GIM3E [54] or  ... 
doi:10.1371/journal.pone.0139665 pmid:26457579 pmcid:PMC4601694 fatcat:mz654wrpcraofmtj5o5wycv2fq

A Genome-Scale Metabolic Model Accurately Predicts Fluxes in Central Carbon Metabolism under Stress Conditions

Thomas C.R. Williams, Mark G. Poolman, Andrew J.M. Howden, Markus Schwarzlander, David A. Fell, R. George Ratcliffe, Lee J. Sweetlove
2010 Plant Physiology  
It is concluded that constraints-based genome-scale modeling can be used to predict flux changes in central carbon metabolism under stress conditions.  ...  Under both conditions, the genome-scale model was able to predict both the direction and magnitude of the changes in flux: namely, increased TCA cycle and decreased phosphoenolpyruvate carboxylase flux  ...  Igor Libourel (University of Minnesota) for stimulating discussions and advice on analyzing mixed pools of labeled and unlabeled proteins.  ... 
doi:10.1104/pp.110.158535 pmid:20605915 pmcid:PMC2938150 fatcat:v6uv6vixgzehljuxyxevwgjg4y

Bayesian Metabolic Flux Analysis reveals intracellular flux couplings [article]

Markus Heinonen, Maria Osmala, Henrik Mannerström, Janne Wallenius, Samuel Kaski, Juho Rousu, Harri Lähdesmäki
2018 arXiv   pre-print
Our model is a plug-in replacement to conventional metabolic balance methods, such as flux balance analysis (FBA).  ...  Our experiments indicate that we can characterise the genome-scale flux covariances, reveal flux couplings, and determine more intracellular unobserved fluxes in C. acetobutylicum from 13C data than flux  ...  direction is still constrained) while the rest 11 fluxes are constrained according to the measurements (leave-one-out), and (C) a model with all 12 13C MFA determined internal fluxes constrained to their  ... 
arXiv:1804.06673v1 fatcat:fhpug4e3fvhqbhm55twg42zaqq

Approaches to Computational Strain Design in the Multiomics Era

Peter C. St. John, Yannick J. Bomble
2019 Frontiers in Microbiology  
There is therefore a growing interest in model-aided design, in which modeling frameworks from systems biology are used to integrate experimental data and generate effective and non-intuitive design predictions  ...  In particular, we compare methods augmenting flux balance analysis with additional constraints from fluxomic, genomic, and metabolomic datasets and methods employing kinetic representations of individual  ...  Some genome-scale MFA methods leverage metabolism's bow-tie structure to constrain fluxes through peripheral pathways with a high degree of confidence (García Martín et al., 2015; Ando and Garcia Martin  ... 
doi:10.3389/fmicb.2019.00597 pmid:31024467 pmcid:PMC6461008 fatcat:lxsj2py4kzglrlabn6qdhqt3h4

Assessment of transcriptomic constraint-based methods for central carbon flux inference

Siddharth Bhadra-Lobo, Min Kyung Kim, Desmond S. Lun, Rajagopal Subramanyam
2020 PLoS ONE  
Thus, transcriptomic data coupled with constraint-based metabolic modeling is a promising method to obtain intracellular flux estimates in microorganisms, particularly in cases where uptake rates of key  ...  In this paper, we formed a dataset of transcriptomic data coupled with corresponding 13C-MFA flux data for 21 experimental conditions in different unicellular organisms grown on varying carbon substrates  ...  We used iJO1366 [18] as the genome-scale metabolic model. Data and model for B. subtilis.  ... 
doi:10.1371/journal.pone.0238689 pmid:32903284 fatcat:xh2qbazokjg2hfbtglt7bhkfbi

Bayesian metabolic flux analysis reveals intracellular flux couplings

2019 Bioinformatics  
Flux analysis methods commonly place model assumptions on fluxes due to the convenience of formulating the problem as a linear programing model, while many methods do not consider the inherent uncertainty  ...  Metabolic flux balance analysis (FBA) is a standard tool in analyzing metabolic reaction rates compatible with measurements, steady-state and the metabolic reaction network stoichiometry.  ...  We experimented with the three main approaches, and found out that Gibbs sampling has consistently the best performance in genome-scale metabolic models up to 4000 fluxes (data not shown).  ... 
doi:10.1093/bioinformatics/btz315 pmid:31510676 pmcid:PMC6612884 fatcat:fxsmhal5tneall4g3mvxs4sazy

Mapping Salmonella typhimurium pathways using 13C metabolic flux analysis

Daniela M. Correia, Cintia R. Sargo, Adilson J. Silva, Sophia T. Santos, Roberto C. Giordano, Eugénio C. Ferreira, Teresa C. Zangirolami, Marcelo P.A. Ribeiro, Isabel Rocha
2019 Metabolic Engineering  
In silico simulations, using Optflux and pFBA as simulation method, allowed to study the performance of the genome-scale metabolic model.  ...  The experiments were carried out in a 2L bioreactor, using defined medium enriched with 20% 13C-labeled glucose.  ...  ), a limitation that seems to be common to many genome-scale models.  ... 
doi:10.1016/j.ymben.2018.11.011 pmid:30529284 fatcat:cged66kgh5dztcnpnnoi6qecay

Strategies for investigating the plant metabolic network with steady-state metabolic flux analysis: lessons from an Arabidopsis cell culture and other systems

N. J. Kruger, S. K. Masakapalli, R. G. Ratcliffe
2011 Journal of Experimental Botany  
considerations relating to data collection, the modelling process that allows a set of metabolic fluxes to be deduced from the labelling data, and the interpretation of flux maps.  ...  While statistically robust protocols for the application of steady-state MFA to plant tissues have been developed by several research groups, the implementation of the method is still far from routine.  ...  Acknowledgements SKM acknowledges financial support from the University of Oxford (Clarendon Scholarship), Exeter College (Mr Krishna Pathak Scholarship), and a UK Overseas Research Student award.  ... 
doi:10.1093/jxb/err382 pmid:22140245 fatcat:xqbqyw52lreofncr3qntdhhzve

Large-scale 13C-flux analysis reveals mechanistic principles of metabolic network robustness to null mutations in yeast

Lars M Blank, Lars Kuepfer, Uwe Sauer
2005 Genome Biology  
Here we identify key experiments in a systems biology approach with a genome-scale model of Saccharomyces cerevisiae metabolism, thereby reducing the workload for experimental network analyses and functional  ...  Genome-scale 13C flux analysis revealed that about half of the 745 biochemical reactions were active during growth on glucose, but that alternative pathways exist for only 51 gene-encoded reactions with  ...  Acknowledgements We are grateful to Eckhard Boles for providing the mae1 mutant. LarsM.  ... 
doi:10.1186/gb-2005-6-6-r49 pmid:15960801 pmcid:PMC1175969 fatcat:53rfhzkowfcjjnfk3zm7t4wqsa
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