TY - JOUR
TI - Uniform sampling of steady-state flux spaces: means to design experiments and to interpret enzymopathies.
AU - Price, Nathan D.
AU - Schellenberger, Jan
AU - Palsson, Bernhard O.
T2 - Biophysical journal
AB - Reconstruction of genome-scale metabolic networks is now possible using multiple different data types. Constraint-based modeling is an approach to interrogate capabilities of reconstructed networks by constraining possible cellular behavior through the imposition of physicochemical laws. As a result, a steady-state flux space is defined that contains all possible functional states of the network. Uniform random sampling of the steady-state flux space allows for the unbiased appraisal of its contents. Monte Carlo sampling of the steady-state flux space of the reconstructed human red blood cell metabolic network under simulated physiologic conditions yielded the following key results: 1), probability distributions for the values of individual metabolic fluxes showed a wide variety of shapes that could not have been inferred without computation; 2), pairwise correlation coefficients were calculated between all fluxes, determining the level of independence between the measurement of any two fluxes, and identifying highly correlated reaction sets; and 3), the network-wide effects of the change in one (or a few) variables (i.e., a simulated enzymopathy or fixing a flux range based on measurements) were computed. Mathematical models provide the most compact and informative representation of a hypothesis of how a cell works. Thus, understanding model predictions clearly is vital to driving forward the iterative model-building procedure that is at the heart of systems biology. Taken together, the Monte Carlo sampling procedure provides a broadening of the constraint-based approach by allowing for the unbiased and detailed assessment of the impact of the applied physicochemical constraints on a reconstructed network.
DA - 2004///
PY - 2004
DO - 10.1529/biophysj.104.043000
VL - 87
IS - 4
SP - 2172
EP - 2186
J2 - Biophys J
LA - eng
KW - *Models, Biological
KW - *Models, Statistical
KW - Animals
KW - Blood Proteins/*metabolism
KW - Computer Simulation
KW - Erythrocytes/*physiology
KW - Gene Expression Regulation, Enzymologic/*physiology
KW - Humans
KW - Metabolism, Inborn Errors/*enzymology
KW - Multienzyme Complexes/metabolism
KW - Sample Size
KW - Signal Transduction/*physiology
ER -