On Friday, 11 February 2011, Prof Raul Conejeros of the Pontificia Universidad Católica de Valparaíso gave a talk on the Effects of Genetic Regulation on Metabolic Control.
Metabolic network analysis is a systemic approach to biological metabolic pathways, where dynamic mass balances account for metabolite concentration variation within the cellular system. Classical metabolic control analysis (MCA) introduces a sensitivity measure for changes in any parameter in the cellular system. Thus, changes in enzyme amounts and metabolite concentrations have a direct effect on enzyme activity. The highest control coefficient obtained with MCA yields the controlling step in the steady-state condition. The work presented is a first attempt to extend MCA to compute control indices, considering changes in enzyme activity dependent on their level of expression. This is achieved by deriving a sensitivity measure of the changes in metabolic behaviour with the changes in enzyme expression at the genomic control level. A case study is shown where an integrated model for glycolysis and the lac operon is considered. In this case study, the dynamic simulation for the lactose intake and its transformation into other metabolites is considered. Furthermore, β-galactosidase and permease production regulations are included and the integrated effects are obtained by computing control coefficients and elasticities using MCA theory and by computing the sensitivity effects of the enzyme expression on the metabolic system for the processing of lactose. Thus the controlling steps are obtained. The analysis is applied in steady-state at each point in the time frame of the dynamic simulation. Results show that, as expected, the controlling steps differ from classical MCA analysis, showing that the control is kept at a genome expression level, and not at the metabolic level. Future work considers extending the analysis to a fully dynamic framework.