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Journal ArticleDOI

Network analysis of intermediary metabolism using linear optimization. I. Development of mathematical formalism.

21 Feb 1992-Journal of Theoretical Biology (J Theor Biol)-Vol. 154, Iss: 4, pp 421-454
TL;DR: Analysis of metabolic networks using linear optimization theory allows one to quantify and understand the limitations imposed on the cell by its metabolic stoichiometry, and to understand how the flux through each pathway influences the overall behavior of metabolism.
About: This article is published in Journal of Theoretical Biology.The article was published on 1992-02-21 and is currently open access. It has received 255 citations till now.
Citations
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Journal ArticleDOI
TL;DR: This protocol provides a helpful manual for all stages of the reconstruction process and presents a comprehensive protocol describing each step necessary to build a high-quality genome-scale metabolic reconstruction.
Abstract: Network reconstructions are a common denominator in systems biology. Bottom–up metabolic network reconstructions have been developed over the last 10 years. These reconstructions represent structured knowledge bases that abstract pertinent information on the biochemical transformations taking place within specific target organisms. The conversion of a reconstruction into a mathematical format facilitates a myriad of computational biological studies, including evaluation of network content, hypothesis testing and generation, analysis of phenotypic characteristics and metabolic engineering. To date, genome-scale metabolic reconstructions for more than 30 organisms have been published and this number is expected to increase rapidly. However, these reconstructions differ in quality and coverage that may minimize their predictive potential and use as knowledge bases. Here we present a comprehensive protocol describing each step necessary to build a high-quality genome-scale metabolic reconstruction, as well as the common trials and tribulations. Therefore, this protocol provides a helpful manual for all stages of the reconstruction process.

1,574 citations

Journal ArticleDOI
TL;DR: A predictive algorithm is formulated in order to apply the flux balance model to describe unsteady-state growth and by-product secretion in aerobic batch, fed-batch, and anaerobic batch cultures.
Abstract: Flux balance models of metabolism use stoichiometry of metabolic pathways, metabolic demands of growth, and optimality principles to predict metabolic flux distribution and cellular growth under specified environmental conditions. These models have provided a mechanistic interpretation of systemic metabolic physiology, and they are also useful as a quantitative tool for metabolic pathway design. Quantitative predictions of cell growth and metabolic by-product secretion that are experimentally testable can be obtained from these models. In the present report, we used independent measurements to determine the model parameters for the wild-type Escherichia coli strain W3110. We experimentally determined the maximum oxygen utilization rate (15 mmol of O2 per g [dry weight] per h), the maximum aerobic glucose utilization rate (10.5 mmol of Glc per g [dry weight] per h), the maximum anaerobic glucose utilization rate (18.5 mmol of Glc per g [dry weight] per h), the non-growth-associated maintenance requirements (7.6 mmol of ATP per g [dry weight] per h), and the growth-associated maintenance requirements (13 mmol of ATP per g of biomass). The flux balance model specified by these parameters was found to quantitatively predict glucose and oxygen uptake rates as well as acetate secretion rates observed in chemostat experiments. We have formulated a predictive algorithm in order to apply the flux balance model to describe unsteady-state growth and by-product secretion in aerobic batch, fed-batch, and anaerobic batch cultures. In aerobic experiments we observed acetate secretion, accumulation in the culture medium, and reutilization from the culture medium. In fed-batch cultures acetate is cometabolized with glucose during the later part of the culture period.(ABSTRACT TRUNCATED AT 250 WORDS)

1,128 citations


Cites background from "Network analysis of intermediary me..."

  • ...A metabolic steady state is assumed, in which the metabolic pathway flux leading to the formation of a metabolite and that leading to the degradation of a metabolite must balance, which generates the flux balance equation (3, 13):...

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Journal ArticleDOI
TL;DR: The flux balance methodology allows the quantitative interpretation of metabolic physiology, gives an interpretation of experimental data, provides a guide to metabolic engineering, enables optimal medium formulation, and provides a method for bioprocess optimization.
Abstract: Recently, there has been an increasing interest in stoichiometric analysis of metabolic flux distributions. Flux balance methods only require information about metabolic reaction stoichiometry, metabolic requirements for growth, and the measurement of a few strain–specific parameters. This information determines the domain of stoichiometrically allowable flux distributions that may be taken to define a strain's “metabolic genotype”. Within this domain a single flux distribution is sought based on assumed behavior, such as maximal growth rates. The optimal flux distributions are calculated using linear optimization and may be taken to represent the strain's “metabolic phenotype” under the particular conditions. This flux balance methodology allows the quantitative interpretation of metabolic physiology, gives an interpretation of experimental data, provides a guide to metabolic engineering, enables optimal medium formulation, and provides a method for bioprocess optimization. This spectrum of applications, and its ease of use, makes the metabolic flux balance model a potentially valuable approach for the design and optimization of bioprocesses.

1,006 citations

Journal ArticleDOI
TL;DR: A generic approach to combine numerical optimization methods with biochemical kinetic simulations is described, suitable for use in the rational design of improved metabolic pathways with industrial significance and for solving the inverse problem of metabolic pathways.
Abstract: MOTIVATION The simulation of biochemical kinetic systems is a powerful approach that can be used for: (i) checking the consistency of a postulated model with a set of experimental measurements, (ii) answering 'what if?' questions and (iii) exploring possible behaviours of a model. Here we describe a generic approach to combine numerical optimization methods with biochemical kinetic simulations, which is suitable for use in the rational design of improved metabolic pathways with industrial significance (metabolic engineering) and for solving the inverse problem of metabolic pathways, i.e. the estimation of parameters from measured variables. RESULTS We discuss the suitability of various optimization methods, focusing especially on their ability or otherwise to find global optima. We recommend that a suite of diverse optimization methods should be available in simulation software as no single one performs best for all problems. We describe how we have implemented such a simulation-optimization strategy in the biochemical kinetics simulator Gepasi and present examples of its application. AVAILABILITY The new version of Gepasi (3.20), incorporating the methodology described here, is available on the Internet at http://gepasi.dbs.aber.ac.uk/softw/Gepasi. html. CONTACT prm@aber.ac.uk

722 citations


Cites methods from "Network analysis of intermediary me..."

  • ...A few groups, notably that of Heinrich, have indeed applied analytical optimization methods (e.g. Heinrich et al., 1987, 1997; Schuster and Heinrich, 1987, 1991; Savinell and Palsson, 1992; Klipp and Heinrich, 1994) to several pathway schemes to investigate the conditions for maximal flux, minimal concentrations, and a series of other criteria....

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  • ...…notably that of Heinrich, have indeed applied analytical optimization methods (e.g. Heinrich et al., 1987, 1997; Schuster and Heinrich, 1987, 1991; Savinell and Palsson, 1992; Klipp and Heinrich, 1994) to several pathway schemes to investigate the conditions for maximal flux, minimal…...

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Journal ArticleDOI
TL;DR: Fundamental issues associated with its formulation and use are reviewed and use to compute optimal growth states are reviewed.

565 citations


Cites background or methods from "Network analysis of intermediary me..."

  • ...DOI 10.1016/j.mib.2010.03.003 Introduction Flux balance analysis (FBA) [1] is a widely used approach for studying biochemical networks, in particular the genome-scale metabolic network reconstructions that have been built in the past decade [2,3]....

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  • ...With metabolic models becoming available for a growing number of organisms [5] and high-throughput technologies enabling the construction of many more each year [6], FBA is an important tool for harnessing the knowledge encoded in these models....

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  • ...Available online at www.sciencedirect.com The biomass objective function Adam M Feist1 and Bernhard O Palsson2 Flux balance analysis (FBA) is a mathematical approach for analyzing the flow of metabolites through a metabolic network....

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  • ...of ATP production, (3) minimizing total nutrient uptake, and (4) minimize redox metabolism through minimizing NADH production Linear programming Hybridoma cell line central metabolism (83 reactions, 42 metabolites) [11] (1) Aerobic batch bioreactor with growth, uptake, secretion, and protein production rates [20] Optimization of biomass production can be used to examine growth characteristics and explain observed phenomena [13] 1997 Max....

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  • ...This issue was recognized in the very first paper on large-scale network analysis using FBA [11,12] where a series of selected objective functions were used to find which one fit the data the best....

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References
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Journal ArticleDOI
TL;DR: The production of acetate by aerobically growing E. coli is examined and it is found that when loads are imposed and flux constraints exist either at the level of NADH turnover rate or the activity of a key Krebs cycle enzyme, switching to acetate overflow is predicted.
Abstract: The production of acetate by aerobically growing E. coli is examined. The problem is formulated in terms of a flow network that has as its objective maximal ATP synthesis. It is found that when loads are imposed and flux constraints exist either at the level of NADH turnover rate or the activity of a key Krebs cycle enzyme, switching to acetate overflow is predicted. Moreover, the result found for the latter constraint can be shown to be formally equivalent to a correlation experimentally determined for the specific rate of acetate production by E. coli K-12.

356 citations

Journal ArticleDOI
TL;DR: Consistent values of the maximum growth yield can be derived, irrespective of whether the cultures are energy limited or energy sufficient, and the possibility that the constant maintenance energy term may be estimated from the maximum specific growth rate is considered.
Abstract: The new model proposed to account for the energy requirement for growth includes both a constant maintenance energy term (m) independent of the specific growth rate and a term (m') which decreases linearly with increase in specific growth rate and becomes zero at the maximum specific growth rate. The available data for testing the model do not deviate significantly from the relations predicted. Consistent values of the maximum growth yield (YG) can be derived, irrespective of whether the cultures are energy limited or energy sufficient. Attention is drawn to the possibility that the constant maintenance energy term may be estimated from the maximum specific growth rate.

344 citations

Journal ArticleDOI
TL;DR: Linear programming has been used to examine the interactions between constraints on metabolism in adipocytes and the requirement for efficiency in the conversion of glucose into fat.
Abstract: The requirement for net balance of synthesis, degradation and transport for all intermediates in the pathways from glucose to fat imposes constraints on the balance of fluxes between different pathways. Linear programming has been used to examine the interactions between these constraints on metabolism in adipocytes and the requirement for efficiency in the conversion of glucose into fat. The circumstances under which excessive ATP synthesis would accompany this conversion have been investigated.

308 citations

Book
01 Aug 2018

273 citations

Book ChapterDOI
W.H. Holms1
TL;DR: This chapter reviews the relationship between flux and control at a branch point, efficiency of conversion to biomass, and excretion of acetate, which focuses on the central metabolic pathways of Escherichia coli.
Abstract: Publisher Summary This chapter focuses on the central metabolic pathways of Escherichia coli . The chapter reviews the relationship between flux and control at a branch point, efficiency of conversion to biomass, and excretion of acetate. Provided that the metabolic routes through the central pathways are known, the carbon input and the outputs to biosynthesis, CO 2 , and excreted products can be used to compute the throughput of each step employed. The product of each throughput and growth rate gives the net flux through each individual enzyme of the system. Futile or useful cycles do not affect fluxes through other reactions in the pathways, and fluxes to maintain pool sizes are quantitatively insignificant. The central pathways are divided into two parts which utilize phosphorylated compounds and carboxylic acids, respectively. Carbon sources which feed into the phosphorylated pathways sustain a more efficient conversion to biomass because, in contrast with other carbon sources, they use the central pathways in the manner for which they were originally selected.

265 citations

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Linear optimization theory is a mathematical formalism used to analyze metabolic networks and understand the limitations and behavior of metabolism.