Regulation and control in complex, dynamic metabolic systems: experimental application of the top-down approaches of metabolic control analysis to fatty acid oxidation and ketogenesis.

Metabolic control analysis has provided experimental tools and a precise language to understand and to describe regulation and control quantitatively in complex, dynamic metabolic systems. The top-down approaches of control analysis reduce and simplify the experiments required to analyse: (1) the potential (group control coefficients) of system parameters (blocks of reactions) to control system variables (fluxes, metabolite concentrations); (2) the sensitivity (group elasticity coefficients) of those blocks of reactions to the action of direct and/or indirect effectors and (3) the regulation of system variables, fluxes through blocks of reactions (partial response coefficients) or through the entire pathway (group response coefficients), by internal or external effectors. Although metabolic control analysis expresses regulation and control in terms of response or control coefficients, which are mathematically derived and have numerical values, the two terms are mathematically indistinguishable. In this paper, we define regulation and control as a consequence of hierarchy and not of mathematical function and analyse a conceptually simplified experimental system to demonstrate our distinction.