DEFINING CONTROL COEFFICIENTS IN NONIDEAL METABOLIC PATHWAYS

The extent to which an enzyme controls a flux has been defined as the effect on that flux of a small modulation of the activity of that enzyme divided by the magnitude of the modulation. We here show that in pathways with metabolic channelling or high enzyme concentrations and conserved moieties involving both enzymic and non-enzymic species, this definition is ambiguous; the magnitude of the corresponding flux control coefficient depends on how the enzyme activity is modulated. This is illustrated with two models of biochemically relevant pathways, one in which dynamic metabolite channelling plays a role, and one with a moiety-conserved cycle. To avoid such ambiguity, we view biochemical pathways in a more detailed manner, i.e., as a network of elemental steps. We define 'elemental control coefficients' in terms of the effect on a flux of an equal modulation of the forward and reverse rate constant of any such elemental step (which may correspond to transitions between enzyme states). This elemental control coefficient is independent of the method of modulation. We show how metabolic control analysis can proceed when formulated in terms of the elemental control coefficients and how the traditional control coefficients are related to these elemental control coefficients, An 'impact' control coefficient is defined which quantifies the effect of an activation of all elemental processes in which an enzyme is involved. It equals the sum of the corresponding elemental control coefficients. In ideal metabolic pathways this impact control coefficient reduces to the traditional flux control coefficient. Differences between the traditional control coefficients are indicative of non-ideality of a metabolic pathway, i.e. of channelling or high enzyme concentrations.