Manipulating Metabolic Fluxes

Strategies for biotechnologically manipulating metabolic fluxes are critically examined in relation to a model system. The common idea of first identifying the rate-limiting enzyme in the biosynthetic pathway to a desired end product, and then increasing its activity, is shown to be completely ineffective: such manipulation typically produces only trivial changes in flux. Manipulating the activities of all of the enzymes in a biosynthetic pathway by amounts calculated to increase a desired flux while leaving all other fluxes and all concentrations unchanged is potentially effective, and can be applied to any system without regard to its regulatory design. However, it requires accurate knowledge of the initial state of the system and the ability to make precise changes to numerous activities. The classical information about the regulatory mechanisms that exist in living organisms suggests that one can make much simpler manipulations, involving only the steps that remove the desired end-product, with almost equally satisfactory results.