title: Metabolomics integrated elementary flux mode analysis in large metabolic networks.
abstract: Elementary flux modes (EFMs) are non-decomposable steady-state pathways in metabolic networks. They characterize phenotypes, quantify robustness or identify engineering targets. An EFM analysis (EFMA) is currently restricted to medium-scale models, as the number of EFMs explodes with the network's size. However, many topologically feasible EFMs are biologically irrelevant. We present thermodynamic EFMA (tEFMA), which calculates only the small(er) subset of thermodynamically feasible EFMs. We integrate network embedded thermodynamics into EFMA and show that we can use the metabolome to identify and remove thermodynamically infeasible EFMs during an EFMA without losing biologically relevant EFMs. Calculating only the thermodynamically feasible EFMs strongly reduces memory consumption and program runtime, allowing the analysis of larger networks. We apply tEFMA to study the central carbon metabolism of E. coli and find that up to 80% of its EFMs are thermodynamically infeasible. Moreover, we identify glutamate dehydrogenase as a bottleneck, when E. coli is grown on glucose and explain its inactivity as a consequence of network embedded thermodynamics. We implemented tEFMA as a Java package which is available for download at https://github.com/mpgerstl/tEFMA.
authors.affiliation: 1] Austrian Centre of Industrial Biotechnology, Vienna, Austria, EU [2] Department of Biotechnology, University of Natural Resources and Life Sciences, Vienna, Austria, EU.
authors.forename: Matthias P
authors.initials: MP
authors.lastname: Gerstl
authors.affiliation: 1] Austrian Centre of Industrial Biotechnology, Vienna, Austria, EU [2] Department of Biotechnology, University of Natural Resources and Life Sciences, Vienna, Austria, EU.
authors.forename: David E
authors.initials: DE
authors.lastname: Ruckerbauer
authors.affiliation: 1] Austrian Centre of Industrial Biotechnology, Vienna, Austria, EU [2] Department of Biotechnology, University of Natural Resources and Life Sciences, Vienna, Austria, EU.
authors.forename: Diethard
authors.initials: D
authors.lastname: Mattanovich
authors.affiliation: 1] Austrian Centre of Industrial Biotechnology, Vienna, Austria, EU [2] Department of Biotechnology, University of Natural Resources and Life Sciences, Vienna, Austria, EU.
authors.forename: Christian
authors.initials: C
authors.lastname: Jungreuthmayer
authors.affiliation: 1] Austrian Centre of Industrial Biotechnology, Vienna, Austria, EU [2] Department of Biotechnology, University of Natural Resources and Life Sciences, Vienna, Austria, EU.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Zanghellini
mesh_terms: D000465:Algorithms; D019295:Computational Biology; D004926:Escherichia coli / Q000201:enzymology / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D005969:Glutamate Dehydrogenase / Q000378:metabolism*; D053858:Metabolic Networks and Pathways; D055432:Metabolomics; D008954:Models, Biological; D013816:Thermodynamics
chemical_list: D005969:Glutamate Dehydrogenase; D005947:Glucose