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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: The tools discussed in this review for investigating redox metabolism provide the basis for studies aiming at a deeper understanding of the interplay between synthetically active enzymes and metabolic networks.
Abstract: Whole-cell biocatalysis utilizes native or recombinant enzymes produced by cellular metabolism to perform synthetically interesting reactions. Besides hydrolases, oxidoreductases represent the most applied enzyme class in industry. Oxidoreductases are attributed a high future potential, especially for applications in the chemical and pharmaceutical industries, as they enable highly interesting chemistry (e.g., the selective oxyfunctionalization of unactivated C–H bonds). Redox reactions are characterized by electron transfer steps that often depend on redox cofactors as additional substrates. Their regeneration typically is accomplished via the metabolism of whole-cell catalysts. Traditionally, studies towards productive redox biocatalysis focused on the biocatalytic enzyme, its activity, selectivity, and specificity, and several successful examples of such processes are running commercially. However, redox cofactor regeneration by host metabolism was hardly considered for the optimization of bio...

98 citations

Journal ArticleDOI
TL;DR: A Bayesian objective function discrimination technique can be applied to any bacterium to test a variety of different possible objective functions, and minimization of the production rate of redox potential was determined to be the most probable objective function.
Abstract: Motivation: A critical component of in silico analysis of underdetermined metabolic systems is the identification of the appropriate objective function. A common assumption is that the objective of the cell is to maximize growth. This objective function has been shown to be consistent in a few limited experimental cases, but may not be universally appropriate. Here a method is presented to quantitatively determine the most probable objective function. Results: The genome-scale metabolism of Escherichia coli growing on succinate was used as a case-study for analysis. Five different objective functions, including maximization of growth rate, were chosen based on biological plausibility. A combination of flux balance analysis and linear programming was used to simulate cellular metabolism, which was then compared to independent experimental data using a Bayesian objective function discrimination technique. After comparing rates of oxygen uptake and acetate production, minimization of the production rate of redox potential was determined to be the most probable objective function. Given the appropriate reaction network and experimental data, the discrimination technique can be applied to any bacterium to test a variety of different possible objective functions. Contact: srivasta@engr.uconn.edu Supplementary information: Additional files, code and a program for carrying out model discrimination are available at http://www.engr.uconn.edu/~srivasta/modisc.html.

97 citations


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

  • ...This objective function was implemented by optimizing the exchange flux for uptake of external nutrients (Savinell and Palsson, 1992), succinate in this case....

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  • ...It is also the first use of a Bayesian approach to identify potential metabolic functions....

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  • ...Contact: srivasta@engr.uconn.edu Supplementary information: Additional files, code and a program for carrying out model discrimination are available at http://www.engr. uconn.edu/~srivasta/modisc.html....

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  • ...In addition, instead of using a heuristic approach to choose the best objective function (Savinell and Palsson, 1992), a single value, the posterior probability share, is used....

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  • ...…et al., 1993, 1999; Holms, 1996; Ibarra et al., 2002; Majewski and Domach, 1990; Mavrovouniotis et al., 1992; Raman et al., 2005; Reed et al., 2003; Sauer et al., 1996, 1998; Savinell and Palsson, 1992; Schilling et al., 2000, 2002; Schilling and Palsson, 2000; Vallino and Stephanopoulos, 2000)....

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Journal ArticleDOI
TL;DR: Methods of algebraically analysing the topology of metabolic networks are presented and the principles of metabolic control analysis are outlined, such as an analysis in terms of time dependent variables and modular analysis.
Abstract: This article gives an overview of recent developments in the modelling of the structure, control and optimality of metabolic networks. In particular, methods of algebraically analysing the topology of such networks are presented. By these methods, conservation relations and elementary modes of functioning (biochemical routes) can be detected. The principles of metabolic control analysis are outlined. Various recent extensions of this theory are presented, such as an analysis in terms of time dependent variables and modular analysis. Evolutionary optimisation principles are applied to explain the catalytic efficiency of single enzymes as well as the structural design of metabolic pathways. Special results concern the optimal distribution of ATP consuming and ATP producing reactions in glycolysis.

97 citations


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

  • ...Therefore, structural approaches to analyse metabolic pathways have attracted ample interest (Reder, 1988; Mavrovouniotis et al., 1990a; Schuster and Schuster, 1991; Savinell and Palsson, 1992; Vallino and Stephanopoulos, 1993)....

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  • ...An alternative method for calculating maximum efficiencies is by using linear optimisation techniques (Fell and Small, 1986; Savinell and Palsson, 1992)....

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  • ...Therefore, structural approaches to analyse metabolic pathways have attracted ample interest (Reder, 1988; Mavrovouniotis et al., 1990a; Schuster and Schuster, 1991; Savinell and Palsson, 1992; Vallino and Stephanopoulos, 1993)....

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Patent
27 Mar 2003
TL;DR: In this article, an in-silico model for determining the physiological function of human cells, including human skeletal muscle cells, was proposed, which includes a data structure relating a plurality of Homo sapiens reactions, a constraint set for the plurality of reactions, and commands for determining a distribution of flux through the reactions that is predictive of a Homo-sapiens physiological function.
Abstract: The invention provides in silico models for determining the physiological function of human cells, including human skeletal muscle cells. The models include a data structure relating a plurality of Homo sapiens reactions, a constraint set for the plurality of Homo sapiens reactions, and commands for determining a distribution of flux through the reactions that is predictive of a Homo sapiens physiological function. A model of the invention can further include a gene database containing information characterizing the associated gene or genes. A regulated Homo sapiens reaction can be represented in a model of the invention by including a variable constraint for the regulated reaction. The invention further provides methods for making an in silico Homo sapiens physiological function using a model of the invention.

95 citations

Journal ArticleDOI
TL;DR: This analysis clarifies the differential needs for central carbon metabolism precursors, glutamine-derived nitrogen, and cofactors such as ATP, NADPH, and NAD+, while also providing justification for various extracellular nutrient uptake behaviors observed in tumors.
Abstract: The study of cancer metabolism has been largely dedicated to exploring the hypothesis that oncogenic transformation rewires cellular metabolism to sustain elevated rates of growth and division. Intense examination of tumors and cancer cell lines has confirmed that many cancer-associated metabolic phenotypes allow robust growth and survival; however, little attention has been given to explicitly identifying the biochemical requirements for cell proliferation in a rigorous manner in the context of cancer metabolism. Using a well-studied hybridoma line as a model, we comprehensively and quantitatively enumerate the metabolic requirements for generating new biomass in mammalian cells; this indicated a large biosynthetic requirement for ATP, NADPH, NAD+, acetyl-CoA, and amino acids. Extension of this approach to serine/glycine and glutamine metabolic pathways suggested lower limits on serine and glycine catabolism to supply one-carbon unit synthesis and significant availability of glutamine-derived carbon for biosynthesis resulting from nitrogen demands alone, respectively. We integrated our biomass composition results into a flux balance analysis model, placing upper bounds on mitochondrial NADH oxidation to simulate metformin treatment; these simulations reproduced several empirically observed metabolic phenotypes, including increased reductive isocitrate dehydrogenase flux. Our analysis clarifies the differential needs for central carbon metabolism precursors, glutamine-derived nitrogen, and cofactors such as ATP, NADPH, and NAD+, while also providing justification for various extracellular nutrient uptake behaviors observed in tumors. Collectively, these results demonstrate how stoichiometric considerations alone can successfully predict empirically observed phenotypes and provide insight into biochemical dynamics that underlie responses to metabolic perturbations.

94 citations


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

  • ...Previous investigations have similarly used minimal stoichiometric models to explore the effects of using a variety of objective functions on metabolic phenotype, the sensitivity of growth rate and other fluxes to perturbations, and the consistency between these in silico predictions and empirical measurements in a mammalian cell line [21, 22]....

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References
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Book
01 Jan 1984
TL;DR: Strodiot and Zentralblatt as discussed by the authors introduced the concept of unconstrained optimization, which is a generalization of linear programming, and showed that it is possible to obtain convergence properties for both standard and accelerated steepest descent methods.
Abstract: This new edition covers the central concepts of practical optimization techniques, with an emphasis on methods that are both state-of-the-art and popular. One major insight is the connection between the purely analytical character of an optimization problem and the behavior of algorithms used to solve a problem. This was a major theme of the first edition of this book and the fourth edition expands and further illustrates this relationship. As in the earlier editions, the material in this fourth edition is organized into three separate parts. Part I is a self-contained introduction to linear programming. The presentation in this part is fairly conventional, covering the main elements of the underlying theory of linear programming, many of the most effective numerical algorithms, and many of its important special applications. Part II, which is independent of Part I, covers the theory of unconstrained optimization, including both derivations of the appropriate optimality conditions and an introduction to basic algorithms. This part of the book explores the general properties of algorithms and defines various notions of convergence. Part III extends the concepts developed in the second part to constrained optimization problems. Except for a few isolated sections, this part is also independent of Part I. It is possible to go directly into Parts II and III omitting Part I, and, in fact, the book has been used in this way in many universities.New to this edition is a chapter devoted to Conic Linear Programming, a powerful generalization of Linear Programming. Indeed, many conic structures are possible and useful in a variety of applications. It must be recognized, however, that conic linear programming is an advanced topic, requiring special study. Another important topic is an accelerated steepest descent method that exhibits superior convergence properties, and for this reason, has become quite popular. The proof of the convergence property for both standard and accelerated steepest descent methods are presented in Chapter 8. As in previous editions, end-of-chapter exercises appear for all chapters.From the reviews of the Third Edition: this very well-written book is a classic textbook in Optimization. It should be present in the bookcase of each student, researcher, and specialist from the host of disciplines from which practical optimization applications are drawn. (Jean-Jacques Strodiot, Zentralblatt MATH, Vol. 1207, 2011)

4,908 citations

Journal ArticleDOI
TL;DR: Analysis of oxidative pathways of glutamine and glutamate showed that extramitochondrial malate is oxidized almost quantitatively to pyruvate + CO2 by NAD(P)+-linked malic enzyme, present in the mitochondria of all tumors tested, but absent in heart, liver, and kidney mitochondria.

374 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.