A Data Integration and Visualization Resource for the Metabolic Network of Synechocystis sp. PCC 6803

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 besides statistical information. In this article, we present a visualization tool for the metabolic network of Synechocystis PCC6803, an important model cyanobacterium for sustainable biofuel production. We illustrate how this metabolic map can be used to integrate experimental and computational data for Synechocystis systems biology and metabolic engineering studies. Additionally, we discuss how this map, and the software infrastructure that we supply with it, can be used in the development of other organism-specific metabolic network visualizations. Besides a Python console package VoNDA (http://vonda.sf.net), we provide a working demonstration of the interactive metabolic map and the associated Synechocystis genome-scale stoichiometric model, as well as various ready-to-visualize microarray data sets, at http://f-a-m-e.org/synechocystis/

Understanding start-up problems in yeast glycolysis

Yeast glycolysis has been the focus of research for decades, yet a number of dynamical aspects of yeast glycolysis remain poorly understood at present. If nutrients are scarce, yeast will provide its catabolic and energetic needs with other pathways, but the enzymes catalysing upper glycolytic fluxes are still expressed. We conjecture that this overexpression facilitates the rapid transition to glycolysis in case of a sudden increase in nutrient concentration. However, if starved yeast is presented with abundant glucose, it can enter into an imbalanced state where glycolytic intermediates keep accumulating, leading to arrested growth and cell death. The bistability between regularly functioning and imbalanced phenotypes has been shown to depend on redox balance. We shed new light on these phenomena with a mathematical analysis of an ordinary differential equation model, including NADH to account for the redox balance. In order to gain qualitative insight, most of the analysis is parameter-free, i.e., without assigning a numerical value to any of the parameters. The model has a subtle bifurcation at the switch between an inviable equilibrium state and stable flux through glycolysis. This switch occurs if the ratio between the flux through upper glycolysis and ATP consumption rate of the cell exceeds a fixed threshold. If the enzymes of upper glycolysis would be barely expressed, our model predicts that there will be no glycolytic flux, even if external glucose would be at growth-permissable levels. The existence of the imbalanced state can be found for certain parameter conditions independent of the mentioned bifurcation. The parameter-free analysis proved too complex to directly gain insight into the imbalanced states, but the starting point of a branch of imbalanced states can be shown to exist in detail. Moreover, the analysis offers the key ingredients necessary for successful numerical continuation, which highlight the existence of this bistability and the influence of the redox balance

Quantitative analysis of amino acid metabolism in liver cancer links glutamate excretion to nucleotide synthesis

Many cancer cells consume glutamine at high rates; counterintuitively, they simultaneously excrete glutamate, the first intermediate in glutamine metabolism. Glutamine consumption has been linked to replenishment of tricarboxylic acid cycle (TCA) intermediates and synthesis of adenosine triphosphate (ATP), but the reason for glutamate excretion is unclear. Here, we dynamically profile the uptake and excretion fluxes of a liver cancer cell line (HepG2) and use genome-scale metabolic modeling for in-depth analysis. We find that up to 30% of the glutamine is metabolized in the cytosol, primarily for nucleotide synthesis, producing cytosolic glutamate. We hypothesize that excreting glutamate helps the cell to increase the nucleotide synthesis rate to sustain growth. Indeed, we show experimentally that partial inhibition of glutamate excretion reduces cell growth. Our integrative approach thus links glutamine addiction to glutamate excretion in cancer and points toward potential drug targets

A proteome-integrated, carbon source dependent genetic regulatory network in Saccharomyces cerevisiae

Integrated regulatory networks can be powerful tools to examine and test properties of cellular systems, such as modelling environmental effects on the molecular bioeconomy, where protein levels are altered in response to changes in growth conditions. Although extensive regulatory pathways and protein interaction data sets exist which represent such networks, few have formally considered quantitative proteomics data to validate and extend them. We generate and consider such data here using a label-free proteomics strategy to quantify alterations in protein abundance for S. cerevisiae when grown on minimal media using glucose, galactose, maltose and trehalose as sole carbon sources. Using a high quality-controlled subset of proteins observed to be differentially abundant, we constructed a proteome-informed network, comprising 1850 transcription factor interactions and 37 chaperone interactions, which defines the major changes in the cellular proteome when growing under different carbon sources. Analysis of the differentially abundant proteins involved in the regulatory network pointed to their significant roles in specific metabolic pathways and function, including glucose homeostasis, amino acid biosynthesis, and carbohydrate metabolic process. We noted strong statistical enrichment in the differentially abundant proteome of targets of known transcription factors associated with stress responses and altered carbon metabolism. This shows how such integrated analysis can lend further experimental support to annotated regulatory interactions, since the proteomic changes capture both magnitude and direction of gene expression change at the level of the affected proteins. Overall this study highlights the power of quantitative proteomics to help define regulatory systems pertinent to environmental conditions

Lactic Acid Bacteria: embarking on 30 more years of research

The 11th International Symposium on Lactic Acid Bacteria Lactic Acid Bacteria play important roles in the pro- duction of food and feed and are increasingly used as health-promoting probiotics. The incessant scientific interest in these microorganisms by academic research groups as well as by industry has resulted in many sig- nificant scientific breakthroughs and has led to new applications. A series of tri-annual symposia on Lactic Acid Bacteria was started in 1983 in order to communi- cate and stimulate research on Lactic Acid Bacteria and their application. These symposia have allowed research- ers from academia and industry to meet, present their work and be informed in an international, open and pleasant atmosphere. Thus, the LAB symposia have, over the years, always presented the state-of-the-art in the field. We have over the past decades witnessed a tre- mendous increase in our understanding of the basic physiology and genetic make-up of these microorgan- isms and, from the turn of the millennium onwards, have been able to apply all ‘omics’ techniques in order to get in-depth understanding of the molecular biology and application potential of lactic acid bacteria. Now, in 2014, we are looking forward to embarking on the next phase and to set the stage for another 30 years of research on this industrially highly relevant group of bacteria. Focus will be on their eminent impor- tance in health and nutrition of humans all over the world. The breadth and richness of LAB research is exemplified by the six selected scientific areas that will be covered at the LAB11 Symposium: Diversity and Evo- lution; Genetics and Physiology; Ecosystems and Sus- tainability; Fermentation and Industrial Application; Host-Microbe Interactions; and Emerging Technologies. Leading, as well as upcoming LAB scientists have been selected to cover the latest developments in these research areas, while renowned scientists from outside the LAB-community have been invited to cover impor- tant emerging fields. For all 11 LAB lectures presented at the LAB11 sym- posium the authors have prepared review-type manu- scripts. These have gone through a standard peer review process, for which we were invited to act as Guest Edi- tors for Microbial Cell Factories. These papers are pre- sented here, online and in a printed version as the “Symposium Proceedings” for all who attend the meet- ing in Egmond aan Zee. We are obliged to the MCF Editor-in-Chief, dr. Antonio Villaverde, to Isobel Peters at BioMed Central and to all our authors and reviewers for the smooth editorial process. We wish you good reading