STRATEGIES FOR MANIPULATING METABOLIC FLUXES IN BIOTECHNOLOGY

Strategies for biotechnologically manipulating metabolic fluxes are cr itically examined in relation to a model system. The common idea of fi rst identifying the rate-limiting enzyme in the biosynthetic pathway t o 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 enz ymes in a biosynthetic pathway by amounts calculated to increase a des ired flux while leaving all other fluxes and all concentrations unchan ged is potentially effective, and can be applied to any system without regard to its regulatory design. however, it requires accurate knowle dge of the initial state of the system and the ability to make precise changes to numerous activities. The classical information about the r egulatory mechanisms that exist in living organisms suggests that one can make much simpler manipulations, involving only the steps that rem ove the desired end-product, with almost equally satisfactory results. (C) 1995 Academic Press, Inc.