Theoretical and conceptual derivation of threshold phenomena and metabolic switching models in a chemostat system

A chemostat cell culture is a polyphasic dispersed system. Three models using net transport and metabolization (T/M) kinetics of hyperbolic form have been described. The first uses only one metabolic pathway and has been studied under various conditions. The second uses two metabolic pathways, with either high or low affinity for the substrate. The third adds excretion of fermentative products to the pathways in model two. Examining the steady states at various dilution rates (D) reveals a critical value (threshold value, Dc), at which the substrate can abruptly invade the cells. If the substrate or its derivatives are active, this abrupt concentration increase may act as a signal at particular growth rates. The second model has been used to study cases where the extracellular compound is a limiting substrate. When part of the substrate was excreted in the form of metabolites, there was a sharp transition between the anabolic and excretion pathways. The excretion pathways are abruptly activated above a critical growth rate. In all cases, the “threshold effects” were related to global and intrinsic characteristics of the culture, represented by the formula . This result may be of practical importance for designing and optimizing biotechnological processes in continuous cultures. The derived model has been effectively used to describe the Crabtree effect in Saccharomyces cerevisiae, which likely implies at least two input pathways of the substrate. The weak affinity pathway is responsible for the respiratory-reproductive transition and leads to the excretion of the fermentation products, including ethanol in yeast and lactate for certain cancers.   Key words: Threshold, metabolic switch, Crabtree effect, substrate transport, respiro-fermentative transition.