title: Systematic assignment of thermodynamic constraints in metabolic network models.
abstract: BACKGROUND
  The availability of genome sequences for many organisms enabled the reconstruction of several genome-scale metabolic network models. Currently, significant efforts are put into the automated reconstruction of such models. For this, several computational tools have been developed that particularly assist in identifying and compiling the organism-specific lists of metabolic reactions. In contrast, the last step of the model reconstruction process, which is the definition of the thermodynamic constraints in terms of reaction directionalities, still needs to be done manually. No computational method exists that allows for an automated and systematic assignment of reaction directions in genome-scale models.
  
  
  RESULTS
  We present an algorithm that - based on thermodynamics, network topology and heuristic rules - automatically assigns reaction directions in metabolic models such that the reaction network is thermodynamically feasible with respect to the production of energy equivalents. It first exploits all available experimentally derived Gibbs energies of formation to identify irreversible reactions. As these thermodynamic data are not available for all metabolites, in a next step, further reaction directions are assigned on the basis of network topology considerations and thermodynamics-based heuristic rules. Briefly, the algorithm identifies reaction subsets from the metabolic network that are able to convert low-energy co-substrates into their high-energy counterparts and thus net produce energy. Our algorithm aims at disabling such thermodynamically infeasible cyclic operation of reaction subnetworks by assigning reaction directions based on a set of thermodynamics-derived heuristic rules. We demonstrate our algorithm on a genome-scale metabolic model of E. coli. The introduced systematic direction assignment yielded 130 irreversible reactions (out of 920 total reactions), which corresponds to about 70% of all irreversible reactions that are required to disable thermodynamically infeasible energy production.
  
  
  CONCLUSIONS
  Although not being fully comprehensive, our algorithm for systematic reaction direction assignment could define a significant number of irreversible reactions automatically with low computational effort. We envision that the presented algorithm is a valuable part of a computational framework that assists the automated reconstruction of genome-scale metabolic models.
authors.affiliation: Institute of Molecular Systems Biology, ETH Zurich, Wolfgang-Pauli-Str, 16, 8093 Zurich, Switzerland. kuemmel@imsb.biol.ethz.ch
authors.forename: Anne
authors.initials: A
authors.lastname: Kümmel
authors.forename: Sven
authors.initials: S
authors.lastname: Panke
authors.forename: Matthias
authors.initials: M
authors.lastname: Heinemann
mesh_terms: D000465:Algorithms; D019295:Computational Biology; D003198:Computer Simulation; D004734:Energy Metabolism; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D008954:Models, Biological; D013816:Thermodynamics