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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 study indicated that the optimal solution space from 62 elementary modes forms a super space which incorporates various mutants including lysine producing strain of C. glutamicum, which allows the maximum theoretical yield for the synthesis of various amino acids.
Abstract: Elementary flux mode (EFM) analysis is a powerful tool to represent the metabolic network structure and can be further utilized for flux analysis. The method enables characterization and quantification of feasible phenotypes in microbes. EFM analysis was employed to characterize the phenotype of Corynebacterium glutamicum to yield various amino acids. The metabolic network of C. glutamicum yielded 62 elementary modes by incorporating the accumulation of amino acids namely, lysine, alanine, valine, glutamine and glutamate. The analysis also allowed us to compute the maximum theoretical yield for the synthesis of various amino acids. These 62 elementary modes were further used to obtain optimal phenotypic space towards accumulation of biomass and lysine. The study indicated that the optimal solution space from 62 elementary modes forms a super space which incorporates various mutants including lysine producing strain of C. glutamicum. The analysis was also extended to obtain sensitivity of the network to variation in the stoichiometry of NADP in the definition of biomass.

11 citations

Journal ArticleDOI
TL;DR: A dynamical FBA-based simulator of hybridoma cell fed-batch cultures predicting the dynamics of biomass growth, substrate consumption, metabolites production and associate intracellular metabolism based on a simplified metabolic network is proposed and results are in agreement with overflow metabolism description available in literature.

11 citations

Book ChapterDOI
TL;DR: The procedure presented in this chapter should enable rapid metabolic flux estimation in any mammalian cell bioreaction network by the stoichiometric approach.
Abstract: Metabolic flux analysis with its ability to quantify cellular metabolism is an attractive tool for accelerating cell line selection, medium optimization, and other bioprocess development activities. In the stoichiometric flux estimation approach, unknown fluxes are determined using intracellular metabolite mass balance expressions and measured extracellular rates. The simplicity of the stoichiometric approach extends its application to most cell culture systems, and the steps involved in metabolic flux estimation by the stoichiometric method are presented in detail in this chapter. Specifically, overdetermined systems are analyzed since the extra measurements can be used to check for gross measurement errors and system consistency. Cell-specific rates comprise the input data for flux estimation, and the logistic modeling approach is described for robust-specific rate estimation in batch and fed-batch systems. A simplified network of mammalian cell metabolism is used to illustrate the flux estimation procedure, and the steps leading up the consistency index determination are presented. If gross measurement errors are detected, a technique for determining the source of gross measurement error is also described. A computer program that performs most of the calculation described in this chapter is presented, and references to flux estimation software are provided. The procedure presented in this chapter should enable rapid metabolic flux estimation in any mammalian cell bioreaction network by the stoichiometric approach.

11 citations

Journal ArticleDOI
TL;DR: A metabolic model for Leptospirillum ferrooxidans was developed based on the genomic information of an analogous iron oxidizing bacteria and on the pathways of ferrous iron oxidation, nitrogen and CO2 assimilation, achieving a very good prediction of the metabolic behavior of this bacterium at steady state.
Abstract: A metabolic model for Leptospirillum ferrooxidans was developed based on the genomic information of an analogous iron oxidizing bacteria and on the pathways of ferrous iron oxidation, nitrogen and CO2 assimilation based on experimental evidence for L. ferrooxidans found in the literature. From this metabolic reconstruction, a stoichiometric model was built, which includes 86 reactions describing the main catabolic and anabolic aspects of its metabolism. The model obtained has 2 degrees of freedom, so two external fluxes were estimated to achieve a determined and observable system. By using the external oxygen consumption rate and the generation flux biomass as input data, a metabolic flux map with a distribution of internal fluxes was obtained. The results obtained were verified with experimental data from the literature, achieving a very good prediction of the metabolic behavior of this bacterium at steady state. Biotechnol. Bioeng. 2010;107:696–706. © 2010 Wiley Periodicals, Inc.

11 citations

Journal ArticleDOI
TL;DR: This mini-review will cover recent advances in both the metabolic and environmental engineering and synthetic biology strategies to couple production with microbial fitness, successful cases for the use of these strategies with ALE to improve product formation, discuss limitations, and future perspectives.
Abstract: Adaptive laboratory evolution (ALE) is a powerful tool to select for strains with growth-coupled phenotypes. When coupled with next-generation sequencing and omic technologies, genotype-to-phenotype relationships and the molecular mechanisms underlying desired complex phenotypes can now be uncovered using ALE. However, in order for ALE to be effective in generating strains with increased productivity, the product-of-interest needs to be coupled with cellular growth or survival. Advances in computational metabolic modeling can now identify metabolic engineering strategies to force the coupling of desired product formation with growth for a wide range of different compounds. Such strategies can potentially be coupled with ALE to further enhance productivity of microbial hosts. In addition to metabolic strategies, if the compound of interest is known to impart beneficial traits to the host, such as stress tolerance, then an environment can be designed to allow product formation to be coupled with growth or survival. This mini-review will cover recent advances in both the metabolic and environmental engineering and synthetic biology strategies to couple production with microbial fitness, successful cases for the use of these strategies with ALE to improve product formation, discuss limitations, and future perspectives.

11 citations

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.