THE METABOLIC PRODUCTIVITY OF THE CELL FACTORY

It is widely accepted that some performance function has been optimize d during the evolution of metabolic pathways. One can study the nature of such a function by analogy with the industrial manufacturing world , in which there have been efforts over recent decades to optimize pro duction chains, and in which it is now accepted that fluxes are not th e only important system variables that determine process efficiency, b ecause inventory turnover must also be considered. Inspired by the par allels between living cells and manufacturing factories, we propose th at fluxes and transit time may have simultaneously been major targets of natural selection in the optimization of the design, structure and kinetic parameters of metabolic pathways. Accordingly we define the ra tio of flux to transit time as a performance index of productivity in metabolic systems: it measures the efficiency with which stocks are ad ministered, and facilitates comparison of a pathway in different stead y states or in different tissues or organisms. For a linear chain of t wo enzymes, at a fixed total equilibrium constant, we have analysed th e variation of flux, transit time and productivity index as functions of the equilibrium constants of the two steps. The results show that o nly the productivity index has a maximum, which represents a good comp romise in optimizing flux and transit time. We have extended control a nalysis to the productivity index and derived the summation theorem th at applies to it. For linear chains of different length with maximum p roductivity index values, the distribution of control coefficients wit h regard to the three parameters has a characteristic profile independ ent of the length of the chain. Finally, this control profile changes when other variables are optimized, and we compare the theoretical res ults with the control profile of the first steps of glycolysis in rat liver. (C) 1996 Academic Press Limited