Engineering the spatial organization of metabolic enzymes: mimicking nature's synergy

A growing body of evidence indicates that many cellular reactions within metabolic pathways are catalyzed not by free-floating ‘soluble’ enzymes, but via one or more membrane-associated multienzyme complexes. This type of macromolecular organization has important implications for the overall efficiency, specificity, and regulation of metabolic pathways. An ever-increasing number of biochemical and genetic studies on primary and secondary metabolism have laid a solid foundation for this model, providing compelling evidence in favor of the so-called channeling of intermediates between enzyme active sites and colocalization of enzymes inside a cell. In this review, we discuss several of nature's most notable multifunctional enzyme systems including the AROM complex and tryptophan synthase, each of which provides new fundamental insights into the structural organization of metabolic machinery within living cells. We then focus on the growing body of literature related to engineering strategies using protein chimeras and post-translational assembly mechanisms. Common among these techniques is the desire to mimic natural enzyme organization for optimizing the production of valuable metabolites with industrial and medical importance.