An extension to the metabolic control theory taking into account correlations between enzyme concentrations

The classical metabolic control theory [Kacser, H. & Burns, J.A. (1973) Symp. Soc. Exp. Biol.27, 65-104; Heinrich, R. & Rapoport, T. (1974) Eur. J. Biochem.42, 89-95.] does not take into account experimental evidence for correlations between enzyme concentrations in the cell. We investigated the implications of two causes of linear correlations: competition between enzymes, which is a mere physical adaptation of the cell to the limitation of resources and space, and regulatory correlations, which result from the existence of regulatory networks. These correlations generate redistribution of enzyme concentrations when the concentration of an enzyme varies; this may dramatically alter the flux and metabolite concentration curves. In particular, negative correlations cause the flux to have a maximum value for a defined distribution of enzyme concentrations. Redistribution coefficients of enzyme concentrations allowed us to calculate the 'combined response coefficient' that quantifies the response of flux or metabolite concentration to a perturbation of enzyme concentration.