title: Integrating tracer-based metabolomics data and metabolic fluxes in a linear fashion via Elementary Carbon Modes.
abstract: Constraints-based modeling is an emergent area in Systems Biology that includes an increasing set of methods for the analysis of metabolic networks. In order to refine its predictions, the development of novel methods integrating high-throughput experimental data is currently a key challenge in the field. In this paper, we present a novel set of constraints that integrate tracer-based metabolomics data from Isotope Labeling Experiments and metabolic fluxes in a linear fashion. These constraints are based on Elementary Carbon Modes (ECMs), a recently developed concept that generalizes Elementary Flux Modes at the carbon level. To illustrate the effect of our ECMs-based constraints, a Flux Variability Analysis approach was applied to a previously published metabolic network involving the main pathways in the metabolism of glucose. The addition of our ECMs-based constraints substantially reduced the under-determination resulting from a standard application of Flux Variability Analysis, which shows a clear progress over the state of the art. In addition, our approach is adjusted to deal with combinatorial explosion of ECMs in genome-scale metabolic networks. This extension was applied to infer the maximum biosynthetic capacity of non-essential amino acids in human metabolism. Finally, as linearity is the hallmark of our approach, its importance is discussed at a methodological, computational and theoretical level and illustrated with a practical application in the field of Isotope Labeling Experiments.
authors.affiliation: CEIT and TECNUN, University of Navarra, Manuel de Lardizabal 15, 20018 San Sebastian, Spain.
authors.forename: Jon
authors.initials: J
authors.lastname: Pey
authors.forename: Angel
authors.initials: A
authors.lastname: Rubio
authors.forename: Constantinos
authors.initials: C
authors.lastname: Theodoropoulos
authors.forename: Marta
authors.initials: M
authors.lastname: Cascante
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Planes
mesh_terms: D000465:Algorithms; D000596:Amino Acids / Q000378:metabolism; D002244:Carbon / Q000378:metabolism; D003198:Computer Simulation; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007553:Isotope Labeling; D016014:Linear Models; D055432:Metabolomics; D008956:Models, Chemical; D049490:Systems Biology / Q000379:methods
chemical_list: D000596:Amino Acids; D002244:Carbon; D005947:Glucose