• Dynamic cumulative activity of transcription factors as a mechanism of quantitative gene regulation.

      He, Feng; Buer, Jan; Zeng, An-Ping; Balling, Rudi; Helmholtz Centre of infection research, Inhoffenstr. 7, D38124 Braunschweig, Germany (2007)
      The regulation of genes in multicellular organisms is generally achieved through the combinatorial activity of different transcription factors. However, the quantitative mechanisms of how a combination of transcription factors controls the expression of their target genes remain unknown.
    • An extended bioreaction database that significantly improves reconstruction and analysis of genome-scale metabolic networks.

      Stelzer, Michael; Sun, Jibin; Kamphans, Tom; Fekete, Sándor P; Zeng, An-Ping (2011-11)
      The bioreaction database established by Ma and Zeng (Bioinformatics, 2003, 19, 270-277) for in silico reconstruction of genome-scale metabolic networks has been widely used. Based on more recent information in the reference databases KEGG LIGAND and Brenda, we upgrade the bioreaction database in this work by almost doubling the number of reactions from 3565 to 6851. Over 70% of the reactions have been manually updated/revised in terms of reversibility, reactant pairs, currency metabolites and error correction. For the first time, 41 spontaneous sugar mutarotation reactions are introduced into the biochemical database. The upgrade significantly improves the reconstruction of genome scale metabolic networks. Many gaps or missing biochemical links can be recovered, as exemplified with three model organisms Homo sapiens, Aspergillus niger, and Escherichia coli. The topological parameters of the constructed networks were also largely affected, however, the overall network structure remains scale-free. Furthermore, we consider the problem of computing biologically feasible shortest paths in reconstructed metabolic networks. We show that these paths are hard to compute and present solutions to find such paths in networks of small and medium size.
    • Reconciliation of genome-scale metabolic reconstructions for comparative systems analysis.

      Oberhardt, Matthew A; Puchałka, Jacek; Martins dos Santos, Vítor A P; Papin, Jason A; Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia, United States of America. (2011-03)
      In the past decade, over 50 genome-scale metabolic reconstructions have been built for a variety of single- and multi- cellular organisms. These reconstructions have enabled a host of computational methods to be leveraged for systems-analysis of metabolism, leading to greater understanding of observed phenotypes. These methods have been sparsely applied to comparisons between multiple organisms, however, due mainly to the existence of differences between reconstructions that are inherited from the respective reconstruction processes of the organisms to be compared. To circumvent this obstacle, we developed a novel process, termed metabolic network reconciliation, whereby non-biological differences are removed from genome-scale reconstructions while keeping the reconstructions as true as possible to the underlying biological data on which they are based. This process was applied to two organisms of great importance to disease and biotechnological applications, Pseudomonas aeruginosa and Pseudomonas putida, respectively. The result is a pair of revised genome-scale reconstructions for these organisms that can be analyzed at a systems level with confidence that differences are indicative of true biological differences (to the degree that is currently known), rather than artifacts of the reconstruction process. The reconstructions were re-validated with various experimental data after reconciliation. With the reconciled and validated reconstructions, we performed a genome-wide comparison of metabolic flexibility between P. aeruginosa and P. putida that generated significant new insight into the underlying biology of these important organisms. Through this work, we provide a novel methodology for reconciling models, present new genome-scale reconstructions of P. aeruginosa and P. putida that can be directly compared at a network level, and perform a network-wide comparison of the two species. These reconstructions provide fresh insights into the metabolic similarities and differences between these important Pseudomonads, and pave the way towards full comparative analysis of genome-scale metabolic reconstructions of multiple species.