Genome-Scale Architecture of Small Molecule Regulatory Networks and the Fundamental Trade-Off between Regulation and Enzymatic Activity.

Cell Reports 2017

Ed Reznik, Dimitris Christodoulou, Joshua E Goldford, Emma Briars, et. al.

Keywords: Elasticity, Enzyme Kinetics, Metabolism, Regulatory Network, Small Molecule Regulation, Trade-Offs

Metabolic flux is in part regulated by endogenous small molecules that modulate the catalytic activity of an enzyme, e.g., allosteric inhibition. In contrast to transcriptional regulation of enzymes, technical limitations have hindered the production of a genome-scale atlas of small molecule-enzyme regulatory interactions. Here, we develop a framework leveraging the vast, but fragmented, biochemical literature to reconstruct and analyze the small molecule regulatory network (SMRN) of the model organism Escherichia coli, including the primary metabolite regulators and enzyme targets.

Parametric studies of metabolic cooperativity in Escherichia coli colonies: Strain and geometric confinement effects.

PloS One 2017

Joseph R Peterson, John A Cole and Zaida Luthey-Schulten

Characterizing the complex spatial and temporal interactions among cells in a biological system (i.e. bacterial colony, microbiome, tissue, etc.) remains a challenge. Metabolic cooperativity in these systems can arise due to the subtle interplay between microenvironmental conditions and the cells’ regulatory machinery, often involving cascades of intra- and extracellular signalling molecules. In the simplest of cases, as demonstrated in a recent study of the model organism Escherichia coli, metabolic cross-feeding can arise in monoclonal colonies of bacteria driven merely by spatial heterogeneity in the availability of growth substrates; namely, acetate, glucose and oxygen.

Constraint-based modeling identifies new putative targets to fight colistin-resistant A. baumannii infections.

Scientific Reports 2017

Luana Presta, Emanuele Bosi, Leila Mansouri, Lenie Dijkshoorn, et. al.

Acinetobacter baumannii is a clinical threat to human health, causing major infection outbreaks worldwide. As new drugs against Gram-negative bacteria do not seem to be forthcoming, and due to the microbial capability of acquiring multi-resistance, there is an urgent need for novel therapeutic targets. Here we have derived a list of new potential targets by means of metabolic reconstruction and modelling of A. baumannii ATCC 19606. By integrating constraint-based modelling with gene expression data, we simulated microbial growth in normal and stressful conditions (i.

Combining Genome-Scale Experimental and Computational Methods To Identify Essential Genes in Rhodobacter sphaeroides.

MSystems 2017

Brian T Burger, Saheed Imam, Matthew J Scarborough, Daniel R Noguera, et. al.

Keywords: Rhodobacter Sphaeroides, Tn-Seq, Gene Disruption, Genomics, Metabolic Modeling, Metabolism, Photosynthetic Bacteria, Proteobacteria

Rhodobacter sphaeroides is one of the best-studied alphaproteobacteria from biochemical, genetic, and genomic perspectives. To gain a better systems-level understanding of this organism, we generated a large transposon mutant library and used transposon sequencing (Tn-seq) to identify genes that are essential under several growth conditions. Using newly developed Tn-seq analysis software (TSAS), we identified 493 genes as essential for aerobic growth on a rich medium. We then used the mutant library to identify conditionally essential genes under two laboratory growth conditions, identifying 85 additional genes required for aerobic growth in a minimal medium and 31 additional genes required for photosynthetic growth.

DistributedFBA.jl: high-level, high-performance flux balance analysis in Julia.

Bioinformatics (Oxford, England) 2017

Laurent Heirendt, Ines Thiele and Ronan M T Fleming

Flux balance analysis and its variants are widely used methods for predicting steady-state reaction rates in biochemical reaction networks. The exploration of high dimensional networks with such methods is currently hampered by software performance limitations.

The JBEI quantitative metabolic modeling library (jQMM): a python library for modeling microbial metabolism.

BMC Bioinformatics 2017

Garrett W Birkel, Amit Ghosh, Vinay S Kumar, Daniel Weaver, et. al.

Keywords: -Omics Data, 13 C Metabolic Flux Analysis, Flux Analysis, Predictive Biology

Modeling of microbial metabolism is a topic of growing importance in biotechnology. Mathematical modeling helps provide a mechanistic understanding for the studied process, separating the main drivers from the circumstantial ones, bounding the outcomes of experiments and guiding engineering approaches. Among different modeling schemes, the quantification of intracellular metabolic fluxes (i.e. the rate of each reaction in cellular metabolism) is of particular interest for metabolic engineering because it describes how carbon and energy flow throughout the cell.

Systems approach to characterize the metabolism of liver cancer stem cells expressing CD133.

Scientific Reports 2017

Wonhee Hur, Jae Yong Ryu, Hyun Uk Kim, Sung Woo Hong, et. al.

Liver cancer stem cells (LCSCs) have attracted attention because they cause therapeutic resistance in hepatocellular carcinoma (HCC). Understanding the metabolism of LCSCs can be a key to developing therapeutic strategy, but metabolic characteristics have not yet been studied. Here, we systematically analyzed and compared the global metabolic phenotype between LCSCs and non-LCSCs using transcriptome and metabolome data. We also reconstructed genome-scale metabolic models (GEMs) for LCSC and non-LCSC to comparatively examine differences in their metabolism at genome-scale.

Mackinac: a bridge between ModelSEED and COBRApy to generate and analyze genome-scale metabolic models.

Bioinformatics 2017

Michael Mundy, Helena Mendes-Soares and Nicholas Chia

Keywords: Flux Balance Analysis, Metabolic Models, Model Reconstruction

Reconstructing and analyzing a large number of genome-scale metabolic models is a fundamental part of the integrated study of microbial communities; however, two of the most widely used frameworks for building and analyzing models use different metabolic network representations. Here we describe Mackinac, a Python package that combines ModelSEED’s ability to automatically reconstruct metabolic models with COBRApy’s advanced analysis capabilities to bridge the differences between the two frameworks and facilitate the study of the metabolic potential of microorganisms.

Efficient estimation of the maximum metabolic productivity of batch systems.

Biotechnology for Biofuels 2017

Peter C St John, Michael F Crowley and Yannick J Bomble

Keywords: Actinobacillus Succinogenes, Dynamic Optimizations, Elementary Flux Modes, Escherichia Coli, Flux Balance Analysis

Production of chemicals from engineered organisms in a batch culture involves an inherent trade-off between productivity, yield, and titer. Existing strategies for strain design typically focus on designing mutations that achieve the highest yield possible while maintaining growth viability. While these methods are computationally tractable, an optimum productivity could be achieved by a dynamic strategy in which the intracellular division of resources is permitted to change with time. New methods for the design and implementation of dynamic microbial processes, both computational and experimental, have therefore been explored to maximize productivity.

Meneco, a Topology-Based Gap-Filling Tool Applicable to Degraded Genome-Wide Metabolic Networks.

PLoS Computational Biology 2017

Sylvain Prigent, Clémence Frioux, Simon M Dittami, Sven Thiele, et. al.

Increasing amounts of sequence data are becoming available for a wide range of non-model organisms. Investigating and modelling the metabolic behaviour of those organisms is highly relevant to understand their biology and ecology. As sequences are often incomplete and poorly annotated, draft networks of their metabolism largely suffer from incompleteness. Appropriate gap-filling methods to identify and add missing reactions are therefore required to address this issue. However, current tools rely on phenotypic or taxonomic information, or are very sensitive to the stoichiometric balance of metabolic reactions, especially concerning the co-factors.

Reliable and efficient solution of genome-scale models of Metabolism and macromolecular Expression.

Scientific Reports 2017

Ding Ma, Laurence Yang, Ronan M T Fleming, Ines Thiele, et. al.

Constraint-Based Reconstruction and Analysis (COBRA) is currently the only methodology that permits integrated modeling of Metabolism and macromolecular Expression (ME) at genome-scale. Linear optimization computes steady-state flux solutions to ME models, but flux values are spread over many orders of magnitude. Data values also have greatly varying magnitudes. Standard double-precision solvers may return inaccurate solutions or report that no solution exists. Exact simplex solvers based on rational arithmetic require a near-optimal warm start to be practical on large problems (current ME models have 70,000 constraints and variables and will grow larger).

Genome-Scale Metabolic Modeling of Archaea Lends Insight into Diversity of Metabolic Function.

Archaea (Vancouver, B.C.) 2017

ShengShee Thor, Joseph R Peterson and Zaida Luthey-Schulten

Decades of biochemical, bioinformatic, and sequencing data are currently being systematically compiled into genome-scale metabolic reconstructions (GEMs). Such reconstructions are knowledge-bases useful for engineering, modeling, and comparative analysis. Here we review the fifteen GEMs of archaeal species that have been constructed to date. They represent primarily members of the Euryarchaeota with three-quarters comprising representative of methanogens. Unlike other reviews on GEMs, we specially focus on archaea. We briefly review the GEM construction process and the genealogy of the archaeal models.

Total of 12 publications. 😄

Personalized Prediction of Proliferation Rates and Metabolic Liabilities in Cancer Biopsies.

Frontiers in Physiology 2016

Christian Diener and Osbaldo Resendis-Antonio

Keywords: NCI60, TCGA, Flux Balance Analysis, Personalized Medicine, Proliferation, Systems Biology

Cancer is a heterogeneous disease and its genetic and metabolic mechanism may manifest differently in each patient. This creates a demand for studies that can characterize phenotypic traits of cancer on a per-sample basis. Combining two large data sets, the NCI60 cancer cell line panel, and The Cancer Genome Atlas, we used a linear interaction model to predict proliferation rates for more than 12,000 cancer samples across 33 different cancers from The Cancer Genome Atlas.

Unique attributes of cyanobacterial metabolism revealed by improved genome-scale metabolic modeling and essential gene analysis.

Proceedings of the National Academy of Sciences of the United States of America 2016

Jared T Broddrick, Benjamin E Rubin, David G Welkie, Niu Du, et. al.

Keywords: Synechococcus Elongatus, TCA Cycle, Constraint-Based Modeling, Cyanobacteria, Photosynthesis

The model cyanobacterium, Synechococcus elongatus PCC 7942, is a genetically tractable obligate phototroph that is being developed for the bioproduction of high-value chemicals. Genome-scale models (GEMs) have been successfully used to assess and engineer cellular metabolism; however, GEMs of phototrophic metabolism have been limited by the lack of experimental datasets for model validation and the challenges of incorporating photon uptake. Here, we develop a GEM of metabolism in S. elongatus using random barcode transposon site sequencing (RB-TnSeq) essential gene and physiological data specific to photoautotrophic metabolism.

Modelling microbial metabolic rewiring during growth in a complex medium.

BMC Genomics 2016

Marco Fondi, Emanuele Bosi, Luana Presta, Diletta Natoli, et. al.

Keywords: Antarctic Bacteria, Flux Balance Analysis, Metabolic Modelling, Pseudoalteromonas Haloplanktis TAC125

In their natural environment, bacteria face a wide range of environmental conditions that change over time and that impose continuous rearrangements at all the cellular levels (e.g. gene expression, metabolism). When facing a nutritionally rich environment, for example, microbes first use the preferred compound(s) and only later start metabolizing the other one(s). A systemic re-organization of the overall microbial metabolic network in response to a variation in the composition/concentration of the surrounding nutrients has been suggested, although the range and the entity of such modifications in organisms other than a few model microbes has been scarcely described up to now.

Multi-omic data integration enables discovery of hidden biological regularities.

Nature Communications 2016

Ali Ebrahim, Elizabeth Brunk, Justin Tan, Edward J O'Brien, et. al.

Rapid growth in size and complexity of biological data sets has led to the ‘Big Data to Knowledge’ challenge. We develop advanced data integration methods for multi-level analysis of genomic, transcriptomic, ribosomal profiling, proteomic and fluxomic data. First, we show that pairwise integration of primary omics data reveals regularities that tie cellular processes together in Escherichia coli: the number of protein molecules made per mRNA transcript and the number of ribosomes required per translated protein molecule.

solveME: fast and reliable solution of nonlinear ME models.

BMC Bioinformatics 2016

Laurence Yang, Ding Ma, Ali Ebrahim, Colton J Lloyd, et. al.

Keywords: Constraint-Based Modeling, Metabolism, Nonlinear Optimization, Proteome, Quasiconvex

Genome-scale models of metabolism and macromolecular expression (ME) significantly expand the scope and predictive capabilities of constraint-based modeling. ME models present considerable computational challenges: they are much (>30 times) larger than corresponding metabolic reconstructions (M models), are multiscale, and growth maximization is a nonlinear programming (NLP) problem, mainly due to macromolecule dilution constraints.

Multi-omics Quantification of Species Variation of Escherichia coli Links Molecular Features with Strain Phenotypes.

Cell Systems 2016

Jonathan M Monk, Anna Koza, Miguel A Campodonico, Daniel Machado, et. al.

Keywords: Escherichia Coli, Genome-Scale Modeling, Metabolic Engineering, Systems Biology

Escherichia coli strains are widely used in academic research and biotechnology. New technologies for quantifying strain-specific differences and their underlying contributing factors promise greater understanding of how these differences significantly impact physiology, synthetic biology, metabolic engineering, and process design. Here, we quantified strain-specific differences in seven widely used strains of E. coli (BL21, C, Crooks, DH5a, K-12 MG1655, K-12 W3110, and W) using genomics, phenomics, transcriptomics, and genome-scale modeling. Metabolic physiology and gene expression varied widely with downstream implications for productivity, product yield, and titer.

MMinte: an application for predicting metabolic interactions among the microbial species in a community.

BMC Bioinformatics 2016

Helena Mendes-Soares, Michael Mundy, Luis Mendes Soares and Nicholas Chia

Keywords: 16S RDNA, Metabolic Network Reconstruction, Microbiome, Network, Predictive Community Modeling

The explosive growth of microbiome research has yielded great quantities of data. These data provide us with many answers, but raise just as many questions. 16S rDNA-the backbone of microbiome analyses-allows us to assess α-diversity, β-diversity, and microbe-microbe associations, which characterize the overall properties of an ecosystem. However, we are still unable to use 16S rDNA data to directly assess the microbe-microbe and microbe-environment interactions that determine the broader ecology of that system.

Genome-Scale Metabolic Model for the Green Alga Chlorella vulgaris UTEX 395 Accurately Predicts Phenotypes under Autotrophic, Heterotrophic, and Mixotrophic Growth Conditions.

Plant Physiology 2016

Cristal Zuñiga, Chien-Ting Li, Tyler Huelsman, Jennifer Levering, et. al.

The green microalga Chlorella vulgaris has been widely recognized as a promising candidate for biofuel production due to its ability to store high lipid content and its natural metabolic versatility. Compartmentalized genome-scale metabolic models constructed from genome sequences enable quantitative insight into the transport and metabolism of compounds within a target organism. These metabolic models have long been utilized to generate optimized design strategies for an improved production process. Here, we describe the reconstruction, validation, and application of a genome-scale metabolic model for C.

Integrated In Silico Analysis of Pathway Designs for Synthetic Photo-Electro-Autotrophy.

PloS One 2016

Michael Volpers, Nico J Claassens, Elad Noor, John van der Oost, et. al.

The strong advances in synthetic biology enable the engineering of novel functions and complex biological features in unprecedented ways, such as implementing synthetic autotrophic metabolism into heterotrophic hosts. A key challenge for the sustainable production of fuels and chemicals entails the engineering of synthetic autotrophic organisms that can effectively and efficiently fix carbon dioxide by using sustainable energy sources. This challenge involves the integration of carbon fixation and energy uptake systems.

From DNA to FBA: How to Build Your Own Genome-Scale Metabolic Model.

Frontiers in Microbiology 2016

Daniel A Cuevas, Janaka Edirisinghe, Chris S Henry, Ross Overbeek, et. al.

Keywords: Flux-Balance Analysis, Genome Annotation, in Silico Modeling, Metabolic Modeling, Metabolic Reconstruction, Model SEED

Microbiological studies are increasingly relying on in silico methods to perform exploration and rapid analysis of genomic data, and functional genomics studies are supplemented by the new perspectives that genome-scale metabolic models offer. A mathematical model consisting of a microbe’s entire metabolic map can be rapidly determined from whole-genome sequencing and annotating the genomic material encoded in its DNA. Flux-balance analysis (FBA), a linear programming technique that uses metabolic models to predict the phenotypic responses imposed by environmental elements and factors, is the leading method to simulate and manipulate cellular growth in silico.

Comparative genome-scale modelling of Staphylococcus aureus strains identifies strain-specific metabolic capabilities linked to pathogenicity.

Proceedings of the National Academy of Sciences of the United States of America 2016

Emanuele Bosi, Jonathan M Monk, Ramy K Aziz, Marco Fondi, et. al.

Keywords: Core Genome, Mathematical Modeling, Pangenome, Pathogenicity, Systems Biology

Staphylococcus aureus is a preeminent bacterial pathogen capable of colonizing diverse ecological niches within its human host. We describe here the pangenome of S. aureus based on analysis of genome sequences from 64 strains of S. aureus spanning a range of ecological niches, host types, and antibiotic resistance profiles. Based on this set, S. aureus is expected to have an open pangenome composed of 7,411 genes and a core genome composed of 1,441 genes.

Systems biology of the structural proteome.

BMC Systems Biology 2016

Elizabeth Brunk, Nathan Mih, Jonathan Monk, Zhen Zhang, et. al.

The success of genome-scale models (GEMs) can be attributed to the high-quality, bottom-up reconstructions of metabolic, protein synthesis, and transcriptional regulatory networks on an organism-specific basis. Such reconstructions are biochemically, genetically, and genomically structured knowledge bases that can be converted into a mathematical format to enable a myriad of computational biological studies. In recent years, genome-scale reconstructions have been extended to include protein structural information, which has opened up new vistas in systems biology research and empowered applications in structural systems biology and systems pharmacology.

Global characterization of in vivo enzyme catalytic rates and their correspondence to in vitro kcat measurements.

Proceedings of the National Academy of Sciences of the United States of America 2016

Dan Davidi, Elad Noor, Wolfram Liebermeister, Arren Bar-Even, et. al.

Keywords: Flux Balance Analysis, Kcat, Kinetic Constants, Proteomics, Turnover Number

Turnover numbers, also known as kcat values, are fundamental properties of enzymes. However, kcat data are scarce and measured in vitro, thus may not faithfully represent the in vivo situation. A basic question that awaits elucidation is: how representative are kcat values for the maximal catalytic rates of enzymes in vivo? Here, we harness omics data to calculate kmax(vivo), the observed maximal catalytic rate of an enzyme inside cells. Comparison with kcat values from Escherichia coli, yields a correlation ofr(2)= 0.

What Makes a Bacterial Species Pathogenic?:Comparative Genomic Analysis of the Genus Leptospira.

PLoS Neglected Tropical Diseases 2016

Derrick E Fouts, Michael A Matthias, Haritha Adhikarla, Ben Adler, et. al.

Leptospirosis, caused by spirochetes of the genus Leptospira, is a globally widespread, neglected and emerging zoonotic disease. While whole genome analysis of individual pathogenic, intermediately pathogenic and saprophytic Leptospira species has been reported, comprehensive cross-species genomic comparison of all known species of infectious and non-infectious Leptospira, with the goal of identifying genes related to pathogenesis and mammalian host adaptation, remains a key gap in the field. Infectious Leptospira, comprised of pathogenic and intermediately pathogenic Leptospira, evolutionarily diverged from non-infectious, saprophytic Leptospira, as demonstrated by the following computational biology analyses: 1) the definitive taxonomy and evolutionary relatedness among all known Leptospira species; 2) genomically-predicted metabolic reconstructions that indicate novel adaptation of infectious Leptospira to mammals, including sialic acid biosynthesis, pathogen-specific porphyrin metabolism and the first-time demonstration of cobalamin (B12) autotrophy as a bacterial virulence factor; 3) CRISPR/Cas systems demonstrated only to be present in pathogenic Leptospira, suggesting a potential mechanism for this clade’s refractoriness to gene targeting; 4) finding Leptospira pathogen-specific specialized protein secretion systems; 5) novel virulence-related genes/gene families such as the Virulence Modifying (VM) (PF07598 paralogs) proteins and pathogen-specific adhesins; 6) discovery of novel, pathogen-specific protein modification and secretion mechanisms including unique lipoprotein signal peptide motifs, Sec-independent twin arginine protein secretion motifs, and the absence of certain canonical signal recognition particle proteins from all Leptospira; and 7) and demonstration of infectious Leptospira-specific signal-responsive gene expression, motility and chemotaxis systems.

PSAMM: A Portable System for the Analysis of Metabolic Models.

PLoS Computational Biology 2016

Jon Lund Steffensen, Keith Dufault-Thompson and Ying Zhang

The genome-scale models of metabolic networks have been broadly applied in phenotype prediction, evolutionary reconstruction, community functional analysis, and metabolic engineering. Despite the development of tools that support individual steps along the modeling procedure, it is still difficult to associate mathematical simulation results with the annotation and biological interpretation of metabolic models. In order to solve this problem, here we developed a Portable System for the Analysis of Metabolic Models (PSAMM), a new open-source software package that supports the integration of heterogeneous metadata in model annotations and provides a user-friendly interface for the analysis of metabolic models.

Total of 15 publications. 😄

FlexFlux: combining metabolic flux and regulatory network analyses.

BMC Systems Biology 2015

Lucas Marmiesse, Rémi Peyraud and Ludovic Cottret

Expression of cell phenotypes highly depends on metabolism that supplies matter and energy. To achieve proper utilisation of the different metabolic pathways, metabolism is tightly regulated by a complex regulatory network composed of diverse biological entities (genes, transcripts, proteins, signalling molecules…). The integrated analysis of both regulatory and metabolic networks appears very insightful but is not straightforward because of the distinct characteristics of both networks. The classical method used for metabolic flux analysis is Flux Balance Analysis (FBA), which is constraint-based and relies on the assumption of steady-state metabolite concentrations throughout the network.

Consistency Analysis of Genome-Scale Models of Bacterial Metabolism: A Metamodel Approach.

PloS One 2015

Miguel Ponce-de-Leon, Jorge Calle-Espinosa, Juli Peretó and Francisco Montero

Genome-scale metabolic models usually contain inconsistencies that manifest as blocked reactions and gap metabolites. With the purpose to detect recurrent inconsistencies in metabolic models, a large-scale analysis was performed using a previously published dataset of 130 genome-scale models. The results showed that a large number of reactions (~22%) are blocked in all the models where they are present. To unravel the nature of such inconsistencies a metamodel was construed by joining the 130 models in a single network.

Networks of energetic and metabolic interactions define dynamics in microbial communities.

Proceedings of the National Academy of Sciences of the United States of America 2015

Mallory Embree, Joanne K Liu, Mahmoud M Al-Bassam and Karsten Zengler

Keywords: Interspecies Interactions, Metabolic Modeling, Methanogens, Microbial Communities, Microbiome

Microorganisms form diverse communities that have a profound impact on the environment and human health. Recent technological advances have enabled elucidation of community diversity at high resolution. Investigation of microbial communities has revealed that they often contain multiple members with complementing and seemingly redundant metabolic capabilities. An understanding of the communal impacts of redundant metabolic capabilities is currently lacking; specifically, it is not known whether metabolic redundancy will foster competition or motivate cooperation.

Systems biology-guided identification of synthetic lethal gene pairs and its potential use to discover antibiotic combinations.

Scientific Reports 2015

Ramy K Aziz, Jonathan M Monk, Robert M Lewis, Suh In Loh, et. al.

Mathematical models of metabolism from bacterial systems biology have proven their utility across multiple fields, for example metabolic engineering, growth phenotype simulation, and biological discovery. The usefulness of the models stems from their ability to compute a link between genotype and phenotype, but their ability to accurately simulate gene-gene interactions has not been investigated extensively. Here we assess how accurately a metabolic model for Escherichia coli computes one particular type of gene-gene interaction, synthetic lethality, and find that the accuracy rate is between 25% and 43%.

The MetaCyc database of metabolic pathways and enzymes and the BioCyc collection of pathway/genome databases.

Nucleic Acids Research 2015

Ron Caspi, Richard Billington, Luciana Ferrer, Hartmut Foerster, et. al.

The MetaCyc database ( is a freely accessible comprehensive database describing metabolic pathways and enzymes from all domains of life. The majority of MetaCyc pathways are small-molecule metabolic pathways that have been experimentally determined. MetaCyc contains more than 2400 pathways derived from >46,000 publications, and is the largest curated collection of metabolic pathways. BioCyc ( is a collection of 5700 organism-specific Pathway/Genome Databases (PGDBs), each containing the full genome and predicted metabolic network of one organism, including metabolites, enzymes, reactions, metabolic pathways, predicted operons, transport systems, and pathway-hole fillers.

BiGG Models: A platform for integrating, standardizing and sharing genome-scale models.

Nucleic Acids Research 2015

Zachary A King, Justin Lu, Andreas Dräger, Philip Miller, et. al.

Genome-scale metabolic models are mathematically-structured knowledge bases that can be used to predict metabolic pathway usage and growth phenotypes. Furthermore, they can generate and test hypotheses when integrated with experimental data. To maximize the value of these models, centralized repositories of high-quality models must be established, models must adhere to established standards and model components must be linked to relevant databases. Tools for model visualization further enhance their utility. To meet these needs, we present BiGG Models (http://bigg.

Cell scale host-pathogen modeling: another branch in the evolution of constraint-based methods.

Frontiers in Microbiology 2015

Neema Jamshidi and Anu Raghunathan

Keywords: Constraint-Based Model, Flux Balance Analysis, Host-Pathogen, Mathematical Models, Omics-Technologies, Optimization Methods, Salmonella Typhimurium, Tuberculosis

Constraint-based models have become popular methods for systems biology as they enable the integration of complex, disparate datasets in a biologically cohesive framework that also supports the description of biological processes in terms of basic physicochemical constraints and relationships. The scope, scale, and application of genome scale models have grown from single cell bacteria to multi-cellular interaction modeling; host-pathogen modeling represents one of these examples at the current horizon of constraint-based methods.

Model-driven discovery of synergistic inhibitors against E. coli and S. enterica serovar Typhimurium targeting a novel synthetic lethal pair, aldA and prpC.

Frontiers in Microbiology 2015

Ramy K Aziz, Valerie L Khaw, Jonathan M Monk, Elizabeth Brunk, et. al.

Keywords: Antibiotic Development, Bacterial Metabolism, Drug Discovery, Metabolic Reconstruction, Model-Based Drug Target Discovery, Pathway Gap Filling, Synthetic Lethality, Systems Biology

Mathematical models of biochemical networks form a cornerstone of bacterial systems biology. Inconsistencies between simulation output and experimental data point to gaps in knowledge about the fundamental biology of the organism. One such inconsistency centers on the gene aldA in Escherichia coli: it is essential in a computational model of E. coli metabolism, but experimentally it is not. Here, we reconcile this disparity by providing evidence that aldA and prpC form a synthetic lethal pair, as the double knockout could only be created through complementation with a plasmid-borne copy of aldA.

Escher: A Web Application for Building, Sharing, and Embedding Data-Rich Visualizations of Biological Pathways.

PLoS Computational Biology 2015

Zachary A King, Andreas Dräger, Ali Ebrahim, Nikolaus Sonnenschein, et. al.

Escher is a web application for visualizing data on biological pathways. Three key features make Escher a uniquely effective tool for pathway visualization. First, users can rapidly design new pathway maps. Escher provides pathway suggestions based on user data and genome-scale models, so users can draw pathways in a semi-automated way. Second, users can visualize data related to genes or proteins on the associated reactions and pathways, using rules that define which enzymes catalyze each reaction.

Tools for visualization and analysis of molecular networks, pathways, and -omics data.

Advances and Applications in Bioinformatics and Chemistry : AABC 2015

Jose M Villaveces, Prasanna Koti and Bianca H Habermann

Keywords: Biological Networks, Genes, Organisms, Protein-Protein Interactions, Proteins, Reactions, Signaling

Biological pathways have become the standard way to represent the coordinated reactions and actions of a series of molecules in a cell. A series of interconnected pathways is referred to as a biological network, which denotes a more holistic view on the entanglement of cellular reactions. Biological pathways and networks are not only an appropriate approach to visualize molecular reactions. They have also become one leading method in -omics data analysis and visualization.

Using Genome-scale Models to Predict Biological Capabilities.

Cell 2015

Edward J O'Brien, Jonathan M Monk and Bernhard O Palsson

Constraint-based reconstruction and analysis (COBRA) methods at the genome scale have been under development since the first whole-genome sequences appeared in the mid-1990s. A few years ago, this approach began to demonstrate the ability to predict a range of cellular functions, including cellular growth capabilities on various substrates and the effect of gene knockouts at the genome scale. Thus, much interest has developed in understanding and applying these methods to areas such as metabolic engineering, antibiotic design, and organismal and enzyme evolution.

Using bioconductor package BiGGR for metabolic flux estimation based on gene expression changes in brain.

PloS One 2015

Anand K Gavai, Farahaniza Supandi, Hannes Hettling, Paul Murrell, et. al.

Predicting the distribution of metabolic fluxes in biochemical networks is of major interest in systems biology. Several databases provide metabolic reconstructions for different organisms. Software to analyze flux distributions exists, among others for the proprietary MATLAB environment. Given the large user community for the R computing environment, a simple implementation of flux analysis in R appears desirable and will facilitate easy interaction with computational tools to handle gene expression data. We extended the R software package BiGGR, an implementation of metabolic flux analysis in R.

Total of 12 publications. 😄

Integration of a constraint-based metabolic model of Brassica napus developing seeds with (13)C-metabolic flux analysis.

Frontiers in Plant Science 2014

Jordan O Hay, Hai Shi, Nicolas Heinzel, Inga Hebbelmann, et. al.

Keywords: 13C-Metabolic Flux Analysis, Carbon Partitioning, Central Metabolism, Constraint-Based Reconstruction and Analysis, Loopless Flux Balance Analysis

The use of large-scale or genome-scale metabolic reconstructions for modeling and simulation of plant metabolism and integration of those models with large-scale omics and experimental flux data is becoming increasingly important in plant metabolic research. Here we report an updated version of bna572, a bottom-up reconstruction of oilseed rape (Brassica napus L.; Brassicaceae) developing seeds with emphasis on representation of biomass-component biosynthesis. New features include additional seed-relevant pathways for isoprenoid, sterol, phenylpropanoid, flavonoid, and choline biosynthesis.

Synthetic biology outside the cell: linking computational tools to cell-free systems.

Frontiers in Bioengineering and Biotechnology 2014

Daniel D Lewis, Fernando D Villarreal, Fan Wu and Cheemeng Tan

Keywords: Artificial Cells, Cell-Free Systems, Computational Modeling, Deterministic and Stochastic Simulations, in Vitro Model, Predictive Modeling, Synthetic Biology

As mathematical models become more commonly integrated into the study of biology, a common language for describing biological processes is manifesting. Many tools have emerged for the simulation of in vivo synthetic biological systems, with only a few examples of prominent work done on predicting the dynamics of cell-free synthetic systems. At the same time, experimental biologists have begun to study dynamics of in vitro systems encapsulated by amphiphilic molecules, opening the door for the development of a new generation of biomimetic systems.

Improving collaboration by standardization efforts in systems biology.

Frontiers in Bioengineering and Biotechnology 2014

Andreas Dräger and Bernhard Ø Palsson

Keywords: Model Databases, Model Formats, Modeling Guidelines, Network Visualization, Ontologies, Software Support

Collaborative genome-scale reconstruction endeavors of metabolic networks would not be possible without a common, standardized formal representation of these systems. The ability to precisely define biological building blocks together with their dynamic behavior has even been considered a prerequisite for upcoming synthetic biology approaches. Driven by the requirements of such ambitious research goals, standardization itself has become an active field of research on nearly all levels of granularity in biology. In addition to the originally envisaged exchange of computational models and tool interoperability, new standards have been suggested for an unambiguous graphical display of biological phenomena, to annotate, archive, as well as to rank models, and to describe execution and the outcomes of simulation experiments.

Current advances in systems and integrative biology.

Computational and Structural Biotechnology Journal 2014

Scott W Robinson, Marco Fernandes and Holger Husi

Keywords: Computational Biology, Data Integration, Pathway Mapping, Systems Biology

Systems biology has gained a tremendous amount of interest in the last few years. This is partly due to the realization that traditional approaches focusing only on a few molecules at a time cannot describe the impact of aberrant or modulated molecular environments across a whole system. Furthermore, a hypothesis-driven study aims to prove or disprove its postulations, whereas a hypothesis-free systems approach can yield an unbiased and novel testable hypothesis as an end-result.

Whole Cell Modeling: From Single Cells to Colonies.

Israel Journal of Chemistry 2014

John A Cole and Zaida Luthey-Schulten

Keywords: Colony Dynamics, Flux Balance Analysis, Kinetics, Metabolism, Stochastic Modeling

A great deal of research over the last several years has focused on how the inherent randomness in movements and reactivity of biomolecules can give rise to unexpected large-scale differences in the behavior of otherwise identical cells. Our own research has approached this problem from two vantage points - a microscopic kinetic view of the individual molecules (nucleic acids, proteins, etc.) diffusing and interacting in a crowded cellular environment; and a broader systems-level view of how enzyme variability can give rise to well-defined metabolic phenotypes.

A genome-scale metabolic flux model of Escherichia coli K-12 derived from the EcoCyc database.

BMC Systems Biology 2014

Daniel S Weaver, Ingrid M Keseler, Amanda Mackie, Ian T Paulsen, et. al.

Constraint-based models of Escherichia coli metabolic flux have played a key role in computational studies of cellular metabolism at the genome scale. We sought to develop a next-generation constraint-based E. coli model that achieved improved phenotypic prediction accuracy while being frequently updated and easy to use. We also sought to compare model predictions with experimental data to highlight open questions in E. coli biology.

A data integration and visualization resource for the metabolic network of Synechocystis sp. PCC 6803.

Plant Physiology 2014

Timo R Maarleveld, Joost Boele, Frank J Bruggeman and Bas Teusink

Data integration is a central activity in systems biology. The integration of genomic, transcript, protein, metabolite, flux, and computational data yields unprecedented information about the system level functioning of organisms. Often, data integration is done purely computationally, leaving the user with little insight in addition to statistical information. In this article, we present a visualization tool for the metabolic network of Synechocystis sp. PCC 6803, an important model cyanobacterium for sustainable biofuel production.

Total of 7 publications. 😄

Sybil--efficient constraint-based modelling in R.

BMC Systems Biology 2013

Gabriel Gelius-Dietrich, Abdelmoneim Amer Desouki, Claus Jonathan Fritzemeier and Martin J Lercher

Constraint-based analyses of metabolic networks are widely used to simulate the properties of genome-scale metabolic networks. Publicly available implementations tend to be slow, impeding large scale analyses such as the genome-wide computation of pairwise gene knock-outs, or the automated search for model improvements. Furthermore, available implementations cannot easily be extended or adapted by users.

Path2Models: large-scale generation of computational models from biochemical pathway maps.

BMC Systems Biology 2013

Finja Büchel, Nicolas Rodriguez, Neil Swainston, Clemens Wrzodek, et. al.

Systems biology projects and omics technologies have led to a growing number of biochemical pathway models and reconstructions. However, the majority of these models are still created de novo, based on literature mining and the manual processing of pathway data.

Solving gap metabolites and blocked reactions in genome-scale models: application to the metabolic network of Blattabacterium cuenoti.

BMC Systems Biology 2013

Miguel Ponce-de-León, Francisco Montero and Juli Peretó

Metabolic reconstruction is the computational-based process that aims to elucidate the network of metabolites interconnected through reactions catalyzed by activities assigned to one or more genes. Reconstructed models may contain inconsistencies that appear as gap metabolites and blocked reactions. Although automatic methods for solving this problem have been previously developed, there are many situations where manual curation is still needed.

GIM3E: condition-specific models of cellular metabolism developed from metabolomics and expression data.

Bioinformatics (Oxford, England) 2013

Brian J Schmidt, Ali Ebrahim, Thomas O Metz, Joshua N Adkins, et. al.

Genome-scale metabolic models have been used extensively to investigate alterations in cellular metabolism. The accuracy of these models to represent cellular metabolism in specific conditions has been improved by constraining the model with omics data sources. However, few practical methods for integrating metabolomics data with other omics data sources into genome-scale models of metabolism have been developed.

Total of 4 publications. 😄