Metabolic transistor: A new strategy for metabolic engineering

Finely controlling a large metabolic flux by a small change in the level or availability of a key participant in the large flux was achieved by a novel metabolic transistor strategy. The fine-tuning of the key participant in the large flux can be accomplished by adding a competitive reaction of a precursor or an intermediate in the biosynthetic pathway of the key participant. To demonstrate this concept, a metabolic transistor based on the electron transport chain (ETC) was built by manipulation of the ubiquinone synthesis pathway in E. coli. The strategy thus provides an in vivo means to genetically control the activity of the ETC and manipulate the production of reduced products. The ubiquinone level of was finely controlled by regulating the competitive pathways for intermediates within the biosynthetic pathway, such as isopentenyl diphosphate (IPP) and 4-hydroxybenzoic acid (4-HB). The advantage of this strategy is that it uses very little cell energy, protein quantity, and carbon flux to control the major metabolic flux of the cell and can be finely tuned for optimal or desired level performance, in the manner of a transistor where a small current change is used to control a big current flow.