Regulation and Redirection of Metabolism: Incorporating regulatory information in flux calculation

摘要

It is well appreciated that cellular metabolism involves interrelated pathway stoicheiometry and complicated regulation loops. Such a complex system imparts a veriety of metabolic characteristics to the living cell. Consequently, to alter metabolism for the production of metabolites, it is essential to gain as much information as possible about pathway stoicheiometry and regulatory kinetics. If the complete details of stoicheiometry and kinetics are known, they can be combined into a mathematical model to predict the behaviour of the cell. Short of complete understanding of regulatory mechanisms, several approaches have been developed to aid the redesign of metabolic pathways. These include pathway analysis (Schuster & Schuster, 1993; Liao et al., 1996; Schuster et al., 1999), flux analysis (Vallino & Stephanopoulos, 1993, Varma et al., 1993), and metabolic control analysis (Kacser & Burns, 1973; Heinrich & Rapoport, 1974). However, none of these approaches are completely satisfactory, primarily because of the complexity of regulatory mechanisms. Hence, successful prediction of flux distribution must take the regulatory mechanisms properly into account. This chapter discusses a promising formalism that aims to predict metabolic flux distribution by incorporating regulatory information in terms of the flux control coefficients into the flux analysis. This approach is most useful for predicting the effect of genetically engineered pathways on flux distribution.