A Network-Based Approach to Cell Metabolism

From Structure to Flux Balances

verfasst von: Oriol Güell

Verlag: Springer International Publishing

Buchreihe : Springer Theses

Enthalten in: Springer Professional "Wirtschaft+Technik" , Springer Professional "Technik" , Springer Professional "Wirtschaft"

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Über dieses Buch

This thesis uses a systems-level approach to study the cellular metabolism, unveiling new mechanisms and responses that were impossible to reach with traditional reductionists procedures.

The results reported here have a potential application in areas like metabolic engineering and disease treatment. They could also be used in determining the accuracy of the gene essentiality of new genome-scale reconstructions.

Different methods and techniques, within the contexts of Systems Biology and the field known as Complex Networks Analysis have been applied in this work to show different features of the robustness of metabolic networks. The specific issues addressed here range from pure topological aspec

ts of the networks themselves to the balance of biochemical fluxes.

Inhaltsverzeichnis

Frontmatter

Chapter 1. Cellular Metabolism at the Systems Level

Abstract

This chapter reviews basic concepts of cellular metabolism. First, an overall view of the architecture of cellular metabolism is given, from the large-scale of Catabolism and Anabolism to biochemical pathways, reactions, and metabolites. Fundamental concepts of chemical kinetics and thermodynamics are mentioned, followed by a brief consideration of key ideas about regulation, control, and evolution of metabolism. Finally, the need for a systems-level approach is discussed. Aims and objectives, together with an outline of this thesis, are included at the end of the chapter.

Oriol Güell

Chapter 2. Methods and Data

Abstract

This chapter describes the basics of the fundamental techniques used in this thesis. It is divided in three parts: (1) complex network tools applied to metabolism, (2) description of Flux Balance Analysis (FBA)—used to compute metabolic fluxes at steady state—and of Flux Variability Analysis—a variant of FBA to bound minimum and maximum fluxes for each reaction—and (3) a description of all the genome-scale metabolic reconstructions analysed in this thesis.

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Chapter 3. Structural Knockout Cascades in Metabolic Networks

Abstract

This chapter presents the analysis of the response of metabolic networks of model organisms to different forms of structural stress, including removals of individual and pairs of reactions and knockouts of single or co-expressed genes.

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Chapter 4. Effects of Reaction Knockouts on Steady States of Metabolism

Abstract

The activity and essentiality of metabolic reactions of two model organisms, Escherichia coli and Mycoplasma pneumoniae, are studied using flux balance analysis in different environments. In particular, synthetic lethal pairs correspond to combinations of active and active or inactive non-essential reactions whose simultaneous deletion causes cell death. Lethal knockouts of pairs of reactions separate in two different groups depending on whether the pair of reactions works as a backup or as a parallel use mechanism, the first corresponding to essential plasticity and the second to essential redundancy. Within this perspective, functional plasticity and redundancy are essential mechanisms underlying the ability to survive of metabolic networks.

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Chapter 5. Detection of Evolution and Adaptation Fingerprints in Metabolic Networks

Abstract

Metabolic fluxes present an heterogeneity that can be exploited to construct metabolic backbones as reduced versions of metabolic networks. These backbones can be analysed to extract important biological information. In this chapter, the disparity filter is applied to two organisms, Escherichia coli and Mycoplasma pneumoniae. Backbones offer information about long-term evolution since they contain the core of ancestral pathways related with energy obtainment optimized by evolution to maximize growth. At the same time, backbones unveil short-term adaptation capabilities to variable external stimuli.

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Chapter 6. Assessing FBA Optimal States in the Feasible Flux Phenotypic Space

Abstract

Optimal growth solutions can be confronted with the whole set of feasible flux phenotypes (FFP), which provides a reference map that helps to assess the likelihood of optimal and high-growth states and their extent of conformity with experimental results. In addition, FFP maps are able to uncover metabolic behaviours that are unreachable using models based on optimality principles. The information content of the full FFP space of metabolic states provides with an entire map to explore and evaluate metabolic behaviour and capabilities, opening new avenues for biotechnological and biomedical applications.

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Chapter 7. Conclusions

Abstract

This thesis presents a study of cell metabolism from a systems-level approach trying to unveil new mechanisms and responses impossible to reach by traditional reductionist procedures. Different methods and analysis techniques have been used, and each one has allowed to extract new insights about the properties of cell metabolism. Tools that belong to the complex network science and Systems Biology have been used. O n what follows, the conclusions of this thesis are given, answering to the objectives stated in Chapter 1.

Oriol Güell

Backmatter

Titel: A Network-Based Approach to Cell Metabolism
verfasst von: Oriol Güell
Verlag: Springer International Publishing
Electronic ISBN: 978-3-319-64000-6
Print ISBN: 978-3-319-63999-4
DOI: https://doi.org/10.1007/978-3-319-64000-6