Method for Determination of the Main Bottleneck Enzyme in a Metabolic Reaction Network by Dynamic Sensitivity Analysis

In fermentation processes, it is important to identify the bottleneck enzyme in a given metabolic reaction network, because increasing its activity would lead to an enhancement in the productivity of a desired metabolite. To efficiently identify the bottleneck enzyme, the present work discusses a systematic approach using dynamic logarithmic gains, i.e., percentage changes in the concentration of the desired metabolite in the response to an infinitesimal percentage change in enzyme activities, as an indicator. A penicillin V fed-batch fermentation model proposed by other researchers was used as an example of application. The calculated results showed that not only the time courses of the dynamic logarithmic gains but also the ranking of the magnitudes of their values is changed with time, implying that the bottleneck enzyme is changed with time in this fermentation process. To determine the bottleneck enzyme from such time-transient behaviors, the dynamic logarithmic gains were integrated over the entire ...