A compact mathematical model of mandelate racemase production and chaperone overexpression in E. coli

摘要

E. coli is commonly used for recombinant protein production, e.g. in the pharmaceutical industry for large-scale production of human insulin. A common problem arises from the formation of (often toxic) protein aggregates. The large number of process parameters complicates finding counter strategies by an empirical trial and error process. More promising seems the application of optimal control strategies based on mathematical modelling of target protein, heat shock proteins, and cell metabolism. However, by now no adequate mathematical model exists. As a first step we propose a small model that comprises the key players of recombinant protein formation, folding, aggregation/disaggregation, and degradation of the target protein mandelate racemase in E. coli. The model also includes the controlled overexpression of selected heat shock proteins (to date the native chaperone systems HSP70 and HSP60 in E. coli). Recombinant production of racemase and overexpression of chaperone systems is initiated by three different induction systems, one for each process. Hence the system has three input signals that later on can be used for control purposes. The model has been parametrised and fitted to appropriate experiments. Despite its limited size, the model explains biomass and chaperone production very well, while racemase production is not (yet) fully covered.