Resolving misconceptions and constraints in growth-coupled bioproduction

Abstract

Growth-coupled bioproduction (GCBP) is a metabolic engineering approach that introduces an obligatory dependency between metabolic activity and production, ensuring a high minimal yield and genetic stability. Here, product yield is primarily limited by pathway constraints, which can be overcome by further metabolic engineering. However, misconceptions persist in understanding GCBP among metabolic and process engineers. Contrary to misperceptions, yield is not stoichiometrically constrained by the growth-restoring enzymatic step, cell division is nonessential for production, and GCBP is compatible with multistage fermentation processes. Finally, GCBP addresses reduced production arising from genetic drift caused by population heterogeneity. Still, challenges remain: the lack of metabolic engineering tools for nonmodel organisms, limited in silico design capabilities, and the existence of uncharacterized metabolism. Nevertheless, by setting a high minimal stoichiometric yield, GCBP facilitates continuous bioproduction. Overall, integrating GCBP with metabolic engineering and improved computational design has the potential to reshape industrial biotechnology toward robust and efficient bioproduction.