Simulation of TCA cycle kinetics

We start our analysis of the TCA cycle kinetics by examining the predicted steady state production of NADH as a function of the NAD and ADP concentrations. From Equation (6.31) we see that there can be no net flux through the TCA cycle when concentration of either NAD or ADP, which serve as substrates for reactions in the cycle, is zero. Thus when the ratios [ATP]/[ADP] and [NADH]/[NAD] are high, we expect the TCA cycle reaction fluxes to be inhibited by simple mass action. In addition, the allosteric inhibition of several enzymes (for example inhibition of pyruvate dehydrogenase by NADH and ACCOA) has important effects. 

The overall control of integrated system behavior by NAD and ADP can be understood based on simulation of the model as follows. We define the rate of NADH production as JDH = JPdh + fsod + Jakgd + Jmdh, and compute the predicted steady state Jnn as a function of [ADP]/A0 and [NAD //V , where A = [ATP] + [ADP] = 10.0 mM and N0 = [NADH] + [NAD] = 2.97 mM are the total concentrations of adenine nucleotide and NAD nucleotide [213], 

The aconitase flux (reaction 3) and the fumarase flux (reaction 8) display overshoots that are small compared to pyruvate dehydrogenase. The aconitase reaction flux reaches a peak value that is only a few percent greater than the final steady state value. The fumarase flux does overshoot the final steady state, but the overshoot is too small to be observed on the scale plotted. This behavior occurs because these reactions are downstream of any reactions directly using NAD as a substrate. Therefore their response is muted compared to reactions that are directly controlled byNAD/NADH. 

The final dehydrogenase in the system (malate dehydrogenase, reaction 11) uses NAD as a substrate and, like pyruvate dehydrogenase, responds sharply to 

---