The application of flux balance analysis in systems biology

Abstract

An increasing number of genome-scale reconstructions of intracellular biochemical networks are being generated. Coupled with these stoichiometric models, several systems-based approaches for probing these reconstructions in silico have been developed. One such approach, called flux balance analysis (FBA), has been effective at predicting systemic phenotypes in the form of fluxes through a reaction network. FBA employs a linear programming (LP) strategy to generate a flux distribution that is optimized toward a particular 'objective,' subject to a set of underlying physicochemical and thermodynamic constraints. Although classical FBA assumes steady-state conditions, several extensions have been proposed in recent years to constrain the allowable flux distributions and enable characterization of dynamic profiles even with minimal kinetic information. Furthermore, FBA coupled with techniques for measuring fluxes in vivo has facilitated integration of computational and experimental approaches, and is allowing pursuit of rational hypothesis-driven research. Ultimately, as we will describe in this review, studying intracellular reaction fluxes allows us to understand network structure and function and has broad applications ranging from metabolic engineering to drug discovery.

Model-based Confirmation of Alternative Substrates of Mitochondrial Electron Transport Chain

“…enzymes and metabolites). The promise of mathematical modeling lies in its potential to quantitatively encompass the multitude of scenarios under which a given biological process may operate and, as a result, elucidate which components contribute to the emerging behavior (1)(2)(3)(4)(5)(6)(7)(8). For this purpose, the spatial separation of metabolites and biochemical reactions into their cellular compartments is an important feature to provide an accurate assessment of energetic limitations that may be lost in decompartmentalized models (9,10).…”

“…For instance, flux balance analysis (FBA), 3 as one of the prominent computational approaches, facilitates the analysis of steady-state fluxes in metabolic networks assumed to operate toward optimizing an objective (e.g. biomass yield) under the constraints captured by the stoichiometric matrix (2,(15)(16)(17)(18)(19). However, perturbed metabolic networks, altered by removing reactions, may not obey the assumptions inherent to FBA.…”

Systems Biology Perspectives on Minimal and Simpler Cells

“…Pál et al used one E. coli GENRE to analyze reductive evolution from the network of E. coli toward the small networks of B. aphidicola and Wigglesworthia glossinidia, which achieved a remarkable accuracy of 80% (162). GENREs have also been used to predict gene essentiality in different organisms and theoretical compositions of minimal media (163).…”

Experimental Definition and Validation of Protein Coding Transcripts in Chlamydomonas reinhardtii

“…FBA is a widely used simulation approach for large-scale, constraint-based metabolic models and has become a standard method in the systems biology field with a long history of success (Gianchandani et al, 2010). Different environmental conditions were modeled by appropriately setting reaction flux constraints in iRC1080 (Supplementary Table S6) including environmental exchanges, non-growth associated ATP maintenance, O 2 photoevolution, starch degradation, and light-or dark-regulated enzymatic reactions (Supplementary Table S5).…”