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Metabolites
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Metabolic Network Models
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Metabolic Network Models

A special issue of Metabolites (ISSN 2218-1989). This special issue belongs to the section "Bioinformatics and Data Analysis".

Deadline for manuscript submissions: closed (31 August 2012) | Viewed by 92119

Special Issue Editor

Prof. Dr. Kyongbum Lee

E-Mail Website
Guest Editor
Department of Chemical and Biological Engineering, Tufts University, Medford, MA 02155, USA
Interests: metabolic engineering; tissue engineering; systems biology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Network models have been instrumental in advancing quantitative knowledge of cellular metabolism by characterizing the systems-level features and properties that arise from the biochemical interactions between metabolites, enzymes and regulatory molecules. Network models are now widely used in both basic and applied studies, ranging from investigations on the evolutionary origins of hierarchical modularity in metabolism to design of synthetic pathways for the overproduction of commercially useful molecules. By exploiting parallel advances in genomics, proteomics and bioinformatics, significant progress has been achieved in modeling metabolic networks, especially in the reconstruction and characterization of whole cell metabolic networks.

Many challenges remain, however, in developing dynamic models capable of predicting the response of cellular metabolism to environmental perturbations or genetic modifications. Given the size and complexity of metabolic networks, new modeling approaches are needed to incorporate existing and new knowledge on regulation, account for uncertainty, and systematically construct an identifiable model whose parameters can be robustly estimated from data. Therefore, this special issue of Metabolites will be dedicated for publishing current advances on dynamic metabolic network models, multi-scale and multi-resolution models, transcriptional and allosteric regulation, integration with signaling and other biochemical networks, parameter estimation from metabolomics data, and modeling of noise and uncertainty.

Prof. Kyongbum Lee
Guest Editor

Keywords

  • metabolic network
  • dynamic model
  • multi-scale
  • multi-resolution
  • model reduction
  • transcriptional regulation
  • allosteric regulation
  • metabolomics data
  • parameter estimation
  • network flexibility
  • robust design

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Published Papers (10 papers)

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Research

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23 pages, 904 KiB  
Article
The Metabolic Interplay between Plants and Phytopathogens
by Guangyou Duan, Nils Christian, Jens Schwachtje, Dirk Walther and Oliver Ebenhöh
Metabolites 2013, 3(1), 1-23; https://doi.org/10.3390/metabo3010001 - 8 Jan 2013
Cited by 34 | Viewed by 11753
Abstract
Plant diseases caused by pathogenic bacteria or fungi cause major economic damage every year and destroy crop yields that could feed millions of people. Only by a thorough understanding of the interaction between plants and phytopathogens can we hope to develop strategies to [...] Read more.
Plant diseases caused by pathogenic bacteria or fungi cause major economic damage every year and destroy crop yields that could feed millions of people. Only by a thorough understanding of the interaction between plants and phytopathogens can we hope to develop strategies to avoid or treat the outbreak of large-scale crop pests. Here, we studied the interaction of plant-pathogen pairs at the metabolic level. We selected five plant-pathogen pairs, for which both genomes were fully sequenced, and constructed the corresponding genome-scale metabolic networks. We present theoretical investigations of the metabolic interactions and quantify the positive and negative effects a network has on the other when combined into a single plant-pathogen pair network. Merged networks were examined for both the native plant-pathogen pairs as well as all other combinations. Our calculations indicate that the presence of the parasite metabolic networks reduce the ability of the plants to synthesize key biomass precursors. While the producibility of some precursors is reduced in all investigated pairs, others are only impaired in specific plant-pathogen pairs. Interestingly, we found that the specific effects on the host’s metabolism are largely dictated by the pathogen and not by the host plant. We provide graphical network maps for the native plant-pathogen pairs to allow for an interactive interrogation. By exemplifying a systematic reconstruction of metabolic network pairs for five pathogen-host pairs and by outlining various theoretical approaches to study the interaction of plants and phytopathogens on a biochemical level, we demonstrate the potential of investigating pathogen-host interactions from the perspective of interacting metabolic networks that will contribute to furthering our understanding of mechanisms underlying a successful invasion and subsequent establishment of a parasite into a plant host. Full article
(This article belongs to the Special Issue Metabolic Network Models)
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29 pages, 1583 KiB  
Article
Medicinal Plants: A Public Resource for Metabolomics and Hypothesis Development
by Eve Syrkin Wurtele, Joe Chappell, A. Daniel Jones, Mary Dawn Celiz, Nick Ransom, Manhoi Hur, Ludmila Rizshsky, Matthew Crispin, Philip Dixon, Jia Liu, Mark P.Widrlechner and Basil J. Nikolau
Metabolites 2012, 2(4), 1031-1059; https://doi.org/10.3390/metabo2041031 - 21 Nov 2012
Cited by 31 | Viewed by 15848
Abstract
Specialized compounds from photosynthetic organisms serve as rich resources for drug development. From aspirin to atropine, plant-derived natural products have had a profound impact on human health. Technological advances provide new opportunities to access these natural products in a metabolic context. Here, we [...] Read more.
Specialized compounds from photosynthetic organisms serve as rich resources for drug development. From aspirin to atropine, plant-derived natural products have had a profound impact on human health. Technological advances provide new opportunities to access these natural products in a metabolic context. Here, we describe a database and platform for storing, visualizing and statistically analyzing metabolomics data from fourteen medicinal plant species. The metabolomes and associated transcriptomes (RNAseq) for each plant species, gathered from up to twenty tissue/organ samples that have experienced varied growth conditions and developmental histories, were analyzed in parallel. Three case studies illustrate different ways that the data can be integrally used to generate testable hypotheses concerning the biochemistry, phylogeny and natural product diversity of medicinal plants. Deep metabolomics analysis of Camptotheca acuminata exemplifies how such data can be used to inform metabolic understanding of natural product chemical diversity and begin to formulate hypotheses about their biogenesis. Metabolomics data from Prunella vulgaris, a species that contains a wide range of antioxidant, antiviral, tumoricidal and anti-inflammatory constituents, provide a case study of obtaining biosystematic and developmental fingerprint information from metabolite accumulation data in a little studied species. Digitalis purpurea, well known as a source of cardiac glycosides, is used to illustrate how integrating metabolomics and transcriptomics data can lead to identification of candidate genes encoding biosynthetic enzymes in the cardiac glycoside pathway. Medicinal Plant Metabolomics Resource (MPM) [1] provides a framework for generating experimentally testable hypotheses about the metabolic networks that lead to the generation of specialized compounds, identifying genes that control their biosynthesis and establishing a basis for modeling metabolism in less studied species. The database is publicly available and can be used by researchers in medicine and plant biology. Full article
(This article belongs to the Special Issue Metabolic Network Models)
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21 pages, 1195 KiB  
Article
Metabolic Consequences of TGFb Stimulation in CulturedPrimary Mouse Hepatocytes Screened from Transcript Data with ModeScore
by Andreas Hoppe, Iryna Ilkavets, Steven Dooley and Hermann-Georg Holzhütter
Metabolites 2012, 2(4), 983-1003; https://doi.org/10.3390/metabo2040983 - 21 Nov 2012
Cited by 2 | Viewed by 7388
Abstract
TGFb signaling plays a major role in the reorganization of liver tissue upon injury and is an important driver of chronic liver disease. This is achieved by a deep impact on a cohort of cellular functions. To comprehensively assess the full range of [...] Read more.
TGFb signaling plays a major role in the reorganization of liver tissue upon injury and is an important driver of chronic liver disease. This is achieved by a deep impact on a cohort of cellular functions. To comprehensively assess the full range of affected metabolic functions, transcript changes of cultured mouse hepatocytes were analyzed with a novel method (ModeScore), which predicts the activity of metabolic functions by scoring transcript expression changes with 987 reference flux distributions, which yielded the following hypotheses. TGFb multiplies down-regulation of most metabolic functions occurring in culture stressed controls. This is especially pronounced for tyrosine degradation, urea synthesis, glucuronization capacity, and cholesterol synthesis. Ethanol degradation and creatine synthesis are down-regulated only in TGFb treated hepatocytes, but not in the control. Among the few TGFb dependently up-regulated functions, synthesis of various collagens is most pronounced. Further interesting findings include: down-regulation of glucose export is postponed by TGFb, TGFb up-regulates the synthesis capacity of ketone bodies only as an early response, TGFb suppresses the strong up-regulation of Vanin, and TGFb induces re-formation of ceramides and sphingomyelin. Full article
(This article belongs to the Special Issue Metabolic Network Models)
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22 pages, 558 KiB  
Article
Ensemble Kinetic Modeling of Metabolic Networks from Dynamic Metabolic Profiles
by Gengjie Jia, Gregory Stephanopoulos and Rudiyanto Gunawan
Metabolites 2012, 2(4), 891-912; https://doi.org/10.3390/metabo2040891 - 12 Nov 2012
Cited by 30 | Viewed by 8459
Abstract
Kinetic modeling of metabolic pathways has important applications in metabolic engineering, but significant challenges still remain. The difficulties faced vary from finding best-fit parameters in a highly multidimensional search space to incomplete parameter identifiability. To meet some of these challenges, an ensemble modeling [...] Read more.
Kinetic modeling of metabolic pathways has important applications in metabolic engineering, but significant challenges still remain. The difficulties faced vary from finding best-fit parameters in a highly multidimensional search space to incomplete parameter identifiability. To meet some of these challenges, an ensemble modeling method is developed for characterizing a subset of kinetic parameters that give statistically equivalent goodness-of-fit to time series concentration data. The method is based on the incremental identification approach, where the parameter estimation is done in a step-wise manner. Numerical efficacy is achieved by reducing the dimensionality of parameter space and using efficient random parameter exploration algorithms. The shift toward using model ensembles, instead of the traditional “best-fit” models, is necessary to directly account for model uncertainty during the application of such models. The performance of the ensemble modeling approach has been demonstrated in the modeling of a generic branched pathway and the trehalose pathway in Saccharomyces cerevisiae using generalized mass action (GMA) kinetics. Full article
(This article belongs to the Special Issue Metabolic Network Models)
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34 pages, 364 KiB  
Article
From Cycling Between Coupled Reactions to the Cross-Bridge Cycle: Mechanical Power Output as an Integral Part of Energy Metabolism
by Frank Diederichs
Metabolites 2012, 2(4), 667-700; https://doi.org/10.3390/metabo2040667 - 8 Oct 2012
Cited by 3 | Viewed by 6712
Abstract
ATP delivery and its usage are achieved by cycling of respective intermediates through interconnected coupled reactions. At steady state, cycling between coupled reactions always occurs at zero resistance of the whole cycle without dissipation of free energy. The cross-bridge cycle can also be [...] Read more.
ATP delivery and its usage are achieved by cycling of respective intermediates through interconnected coupled reactions. At steady state, cycling between coupled reactions always occurs at zero resistance of the whole cycle without dissipation of free energy. The cross-bridge cycle can also be described by a system of coupled reactions: one energising reaction, which energises myosin heads by coupled ATP splitting, and one de-energising reaction, which transduces free energy from myosin heads to coupled actin movement. The whole cycle of myosin heads via cross-bridge formation and dissociation proceeds at zero resistance. Dissipation of free energy from coupled reactions occurs whenever the input potential overcomes the counteracting output potential. In addition, dissipation is produced by uncoupling. This is brought about by a load dependent shortening of the cross-bridge stroke to zero, which allows isometric force generation without mechanical power output. The occurrence of maximal efficiency is caused by uncoupling. Under coupled conditions, Hill’s equation (velocity as a function of load) is fulfilled. In addition, force and shortening velocity both depend on [Ca2+]. Muscular fatigue is triggered when ATP consumption overcomes ATP delivery. As a result, the substrate of the cycle, [MgATP2−], is reduced. This leads to a switch off of cycling and ATP consumption, so that a recovery of [ATP] is possible. In this way a potentially harmful, persistent low energy state of the cell can be avoided. Full article
(This article belongs to the Special Issue Metabolic Network Models)
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16 pages, 5037 KiB  
Article
A Topological Characterization of Medium-Dependent Essential Metabolic Reactions
by Nikolaus Sonnenschein, Carsten Marr and Marc-Thorsten Hütt
Metabolites 2012, 2(3), 632-647; https://doi.org/10.3390/metabo2030632 - 24 Sep 2012
Cited by 8 | Viewed by 7163
Abstract
Metabolism has frequently been analyzed from a network perspective. A major question is how network properties correlate with biological features like growth rates, flux patterns and enzyme essentiality. Using methods from graph theory as well as established topological categories of metabolic systems, we [...] Read more.
Metabolism has frequently been analyzed from a network perspective. A major question is how network properties correlate with biological features like growth rates, flux patterns and enzyme essentiality. Using methods from graph theory as well as established topological categories of metabolic systems, we analyze the essentiality of metabolic reactions depending on the growth medium and identify the topological footprint of these reactions. We find that the typical topological context of a medium-dependent essential reaction is systematically different from that of a globally essential reaction. In particular, we observe systematic differences in the distribution of medium-dependent essential reactions across three-node subgraphs (the network motif signature of medium-dependent essential reactions) compared to globally essential or globally redundant reactions. In this way, we provide evidence that the analysis of metabolic systems on the few-node subgraph scale is meaningful for explaining dynamic patterns. This topological characterization of medium-dependent essentiality provides a better understanding of the interplay between reaction deletions and environmental conditions. Full article
(This article belongs to the Special Issue Metabolic Network Models)
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21 pages, 360 KiB  
Article
Canonical Modeling of the Multi-Scale Regulation of the Heat Stress Response in Yeast
by Luis L. Fonseca, Po-Wei Chen and Eberhard O. Voit
Metabolites 2012, 2(1), 221-241; https://doi.org/10.3390/metabo2010221 - 27 Feb 2012
Cited by 9 | Viewed by 7170
Abstract
Heat is one of the most fundamental and ancient environmental stresses, and response mechanisms are found in prokaryotes and shared among most eukaryotes. In the budding yeast Saccharomyces cerevisiae, the heat stress response involves coordinated changes at all biological levels, from gene [...] Read more.
Heat is one of the most fundamental and ancient environmental stresses, and response mechanisms are found in prokaryotes and shared among most eukaryotes. In the budding yeast Saccharomyces cerevisiae, the heat stress response involves coordinated changes at all biological levels, from gene expression to protein and metabolite abundances, and to temporary adjustments in physiology. Due to its integrative multi-level-multi-scale nature, heat adaptation constitutes a complex dynamic process, which has forced most experimental and modeling analyses in the past to focus on just one or a few of its aspects. Here we review the basic components of the heat stress response in yeast and outline what has been done, and what needs to be done, to merge the available information into computational structures that permit comprehensive diagnostics, interrogation, and interpretation. We illustrate the process in particular with the coordination of two metabolic responses, namely the dramatic accumulation of the protective disaccharide trehalose and the substantial change in the profile of sphingolipids, which in turn affect gene expression. The proposed methods primarily use differential equations in the canonical modeling framework of Biochemical Systems Theory (BST), which permits the relatively easy construction of coarse, initial models even in systems that are incompletely characterized. Full article
(This article belongs to the Special Issue Metabolic Network Models)
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Review

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29 pages, 428 KiB  
Review
Current Understanding of the Formation and Adaptation of Metabolic Systems Based on Network Theory
by Kazuhiro Takemoto
Metabolites 2012, 2(3), 429-457; https://doi.org/10.3390/metabo2030429 - 12 Jul 2012
Cited by 13 | Viewed by 10099
Abstract
Formation and adaptation of metabolic networks has been a long-standing question in biology. With recent developments in biotechnology and bioinformatics, the understanding of metabolism is progressively becoming clearer from a network perspective. This review introduces the comprehensive metabolic world that has been revealed [...] Read more.
Formation and adaptation of metabolic networks has been a long-standing question in biology. With recent developments in biotechnology and bioinformatics, the understanding of metabolism is progressively becoming clearer from a network perspective. This review introduces the comprehensive metabolic world that has been revealed by a wide range of data analyses and theoretical studies; in particular, it illustrates the role of evolutionary events, such as gene duplication and horizontal gene transfer, and environmental factors, such as nutrient availability and growth conditions, in evolution of the metabolic network. Furthermore, the mathematical models for the formation and adaptation of metabolic networks have also been described, according to the current understanding from a perspective of metabolic networks. These recent findings are helpful in not only understanding the formation of metabolic networks and their adaptation, but also metabolic engineering. Full article
(This article belongs to the Special Issue Metabolic Network Models)
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24 pages, 247 KiB  
Review
Stoichiometry Based Steady-State Hepatic Flux Analysis: Computational and Experimental Aspects
by Mehmet A. Orman, John Mattick, Ioannis P. Androulakis, Francois Berthiaume and Marianthi G. Ierapetritou
Metabolites 2012, 2(1), 268-291; https://doi.org/10.3390/metabo2010268 - 14 Mar 2012
Cited by 8 | Viewed by 6995
Abstract
The liver has many complex physiological functions, including lipid, protein and carbohydrate metabolism, as well as bile and urea production. It detoxifies toxic substances and medicinal products. It also plays a key role in the onset and maintenance of abnormal metabolic patterns associated [...] Read more.
The liver has many complex physiological functions, including lipid, protein and carbohydrate metabolism, as well as bile and urea production. It detoxifies toxic substances and medicinal products. It also plays a key role in the onset and maintenance of abnormal metabolic patterns associated with various disease states, such as burns, infections and major traumas. Liver cells have been commonly used in in vitro experiments to elucidate the toxic effects of drugs and metabolic changes caused by aberrant metabolic conditions, and to improve the functions of existing systems, such as bioartificial liver. More recently, isolated liver perfusion systems have been increasingly used to characterize intrinsic metabolic changes in the liver caused by various perturbations, including systemic injury, hepatotoxin exposure and warm ischemia. Metabolic engineering tools have been widely applied to these systems to identify metabolic flux distributions using metabolic flux analysis or flux balance analysis and to characterize the topology of the networks using metabolic pathway analysis. In this context, hepatic metabolic models, together with experimental methodologies where hepatocytes or perfused livers are mainly investigated, are described in detail in this review. The challenges and opportunities are also discussed extensively. Full article
(This article belongs to the Special Issue Metabolic Network Models)
12 pages, 371 KiB  
Review
Human Metabolic Network: Reconstruction, Simulation, and Applications in Systems Biology
by Ming Wu and Christina Chan
Metabolites 2012, 2(1), 242-253; https://doi.org/10.3390/metabo2010242 - 2 Mar 2012
Cited by 8 | Viewed by 8121
Abstract
Metabolism is crucial to cell growth and proliferation. Deficiency or alterations in metabolic functions are known to be involved in many human diseases. Therefore, understanding the human metabolic system is important for the study and treatment of complex diseases. Current reconstructions of the [...] Read more.
Metabolism is crucial to cell growth and proliferation. Deficiency or alterations in metabolic functions are known to be involved in many human diseases. Therefore, understanding the human metabolic system is important for the study and treatment of complex diseases. Current reconstructions of the global human metabolic network provide a computational platform to integrate genome-scale information on metabolism. The platform enables a systematic study of the regulation and is applicable to a wide variety of cases, wherein one could rely on in silico perturbations to predict novel targets, interpret systemic effects, and identify alterations in the metabolic states to better understand the genotype-phenotype relationships. In this review, we describe the reconstruction of the human metabolic network, introduce the constraint based modeling approach to analyze metabolic networks, and discuss systems biology applications to study human physiology and pathology. We highlight the challenges and opportunities in network reconstruction and systems modeling of the human metabolic system. Full article
(This article belongs to the Special Issue Metabolic Network Models)
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