Thus, a better understanding of the lactate consumption phenomena will help in contriving strategies for robust control of cell metabolism and higher protein yields. Previously, we reported development of a mechanistic mathematical model of glycolysis and the pentose phosphate pathway to examine the dynamic U0126 behavior of glucose metabolism. The model considers different isozymes of three key glycolysis enzymes, pyruvate kinase and 6-phosphofructo-2-kinase/fructose-2,6-bisphophatase ) and the allosteric regulations they are subjected to by glycolytic intermediates. All three isozymes of PFK are activated by fructose-2,6-bisphosphate, but only PFKM and PFKL are activated by fructose-1,6-bisphosphate. Three isozymes of PK are activated by F16BP to varying extents while PKM1 is not under such allosteric regulation. PFKFB is a bifunctional enzyme whose kinase and bisphosphatase domains catalyze the formation and hydrolysis reaction of F26BP, respectively. The four isozymes of PFKFB differ in their kinase and phosphatase activities as well as in their sensitivity to feedback inhibition by phosphoenolpyruvate. In addition, several isozymes of PFKFB are subject to post-translational modification by hormonal and growth signaling pathways that modulate the balance between the kinase and phosphatase activities. Thus, each isozyme of PFKFB has a profoundly distinct capacity in modulating PFK activity. We demonstrated that the combination of isozymes of these three glycolytic enzymes, commonly seen in many rapidly growing cells, give rise to bistable behavior in glycolysis activity. Under physiological glucose concentrations, the steady state glycolysis flux may be at a high state or a low state. Although the cells may switch their metabolism between the two flux GSI-IX abmole states, the transition from a high flux state to a low flux state can only occur at glucose concentrations that are outside the physiological range. Our model prediction of bistability is consistent with the experimental observation that a shift from a high flux state to a low flux state was accomplished only by controlling glucose concentration at very low levels. In the current study, we hypothesize that the switch of metabolism in fed-batch culture is a reflection of the bistable behavior described above. The glucose and lactate concentrations in contemporary fed-batch processes often reach levels beyond 30 mM and 100 mM, respectively. Such non-physiological conditions may elicit dynamic responses unseen in vivo. In particular the inhibitory effect of lactate on PFK that is relatively minor in most tissues in vivo may become prominent in fed-batch cultures due to its high level of accumulation. In this work, we extend our previous modeling explorations to the previously unexplored space of glucose and lactate concentrations that spread beyond physiological levels and seek to address the important issue of the controllability of metabolic shift in biopharmaceutical manufacturing. Since lactate consumption occurs through its conversion to pyruvate and oxidation in the tricarboxylic acid cycle, we extended our model to include the TCA cycle and the malate-aspartate shuttles. Metabolic shift in cultured cells largely occurs after the rapid growth period is over. The linkage between metabolism and growth control has been a subject of intense research in the past decade. The v-akt murine thymoma viral oncogene homolog, also known as protein kinase B, is a serine/threonine kinase that plays a key role in multiple cellular processes including cell proliferation and glucose metabolism. AKT exists in an active/phosphorylated form and an inactive/unphosphorylated form. The AKT signaling cascade has been shown to activate the transcription of GLUT1 and mediates the association of hexokinase 1 and 2 with outer mitochondrial membrane.