Digital computer simulation has been used to study the control of two metabolic pathways, the citric acid cycle in rat heart, and glutathione synthesis in sheep red cells. The latter system was of interest because in a particular breed of sheep the red cell glutathione concentration has been shown to be correlated with a high or a low concentration of the initial enzyme in the pathway, even though the Vmax for this enzyme is always much larger than that for the second enzyme.
In both instances control lay largely with the first enzyme in the pathway, which is quasi-irreversible, but in the citric acid cycle an important additional control is the rate of production of NADH by isocitric dehydrogenase and oxoglutarate dehydrogenase. This affects the flux through malate dehydrogenase and hence the rate of formation of oxaloacetate, which is needed for the first reaction of the cycle. The other two dehydrogenases are not sensitive to {NADH} in the conditions simulated.
In arriving at this conclusion a modified version of the "elasticity" (effector strength) parameter (Kacser & Bums, 1973) was found to be very useful. The "sensitivity" (control strength) parameter of these authors was not, however, found to be so useful, in part because conditions in which it may be fully applied do not always exist. This was shown to be so for the pathway of glutathione synthesis in red cells.