Model-based optimization of the recombinant protein production in Pichia pastoris based on dynamic flux balance analysis and elementary process functions

Abstract

Abstract Pichia pastoris is an important host cell for the heterologous expression of recombinant proteins. In order to understand and design optimal biopharmaceutical processes with P. pastoris, unstructured and flux balance analysis (FBA) models have been developed which consider either extracellular fluxes or intracellular fluxes, respectively. In an at-tempt to predict both intracellular and extracellular fluxes, structured models have been introduced, but existing structured models compartmentalize pathways and do not con-sider the metabolic networks in detail. In this paper, we present a model-based optimiza-tion approach for the production of recombinant proteins in P. pastoris. Our approach is based on dynamic flux balance analysis (dFBA) and elementary process functions (EPF). We show that our concept is able to predict both dynamic extracellular concentrations and time-dependent intracellular fluxes in detail with no need for compartmentalization. We also present an efficient solution strategy for our approach.