IReMet-flux: Constraint-based approach for integrating relative metabolite levels into a stoichiometric metabolic models

Abstract

Motivation: Understanding the rerouting of metabolic reaction fluxes upon perturbations has the potential to link changes in molecular state of a cellular system to alteration of growth. Yet, differential flux profiling on a genome-scale level remains one of the biggest challenges in systems biology. This is particularly relevant in plants, for which fluxes in autotrophic growth necessitate time-consuming instationary labeling experiments and costly computations, feasible for small-scale networks. Results: Here we present a computationally and experimentally facile approach, termed iReMet-Flux, which integrates relative metabolomics data in a metabolic model to predict differential fluxes at a genome-scale level. Our approach and its variants complement the flux estimation methods based on radioactive tracer labeling. We employ iReMet-Flux with publically available metabolic profiles to predict reactions and pathways with altered fluxes in photo-autotrophically grown Arabidopsis and four photorespiratory mutants undergoing high-to-low CO2 acclimation. We also provide predictions about reactions and pathways which are most strongly regulated in the investigated experiments. The robustness and variability analyses, tailored to the formulation of iReMet-Flux, demonstrate that the findings provide biologically relevant information that is validated with external measurements of net CO2 exchange and biomass production. Therefore, iReMet-Flux paves the wave for mechanistic dissection of the interplay between pathways of primary and secondary metabolisms at a genome-scale. Availability and Implementation: The source code is available from the authors upon request.