Inferring differences in the distribution of reaction rates across conditions.
Elucidating changes in the distribution of reaction rates in metabolic pathways under different conditions is a central challenge in systems biology. Here we present a method for inferring regulation mechanisms responsible for changes in the distribution of reaction rates across conditions from correlations in time-resolved data. A reversal of correlations between conditions reveals information about regulation mechanisms. With the use of a small in silico hypothetical network, based on only the topology and directionality of a known pathway, several regulation scenarios can be formulated. Confronting these scenarios with experimental data results in a short list of possible pathway regulation mechanisms associated with the reversal of correlations between conditions. This procedure allows for the formulation of regulation scenarios without detailed prior knowledge of kinetics and for the inference of reaction rate changes without rate information. The method was applied to experimental time-resolved metabolomics data from multiple short-term perturbation-response experiments in S. cerevisiae across aerobic and anaerobic conditions. The method's output was validated against a detailed kinetic model of glycolysis in S. cerevisiae, which showed that the method can indeed infer the correct regulation scenario.
Biosystems Data Analysis, Swammerdam Institute for Life Sciences, University of Amsterdam, The Netherlands.
Diana M
DM
Hendrickx
Huub C J
HC
Hoefsloot
Margriet M W B
MM
Hendriks
Daniël J
DJ
Vis
André B
AB
Canelas
Bas
B
Teusink
Age K
AK
Smilde
D019295:Computational Biology / Q000379:methods; D006019:Glycolysis; D007700:Kinetics; D053858:Metabolic Networks and Pathways / Q000502:physiology*; D008954:Models, Biological; D012441:Saccharomyces cerevisiae / Q000378:metabolism; D049490:Systems Biology / Q000379:methods*