Optimal stoichiometric designs of ATP-producing systems as determined by an evolutionary algorithm

The design of metabolic pathways is thought to be the result of an optimiza tion process such that the structure of contemporary metabolic routes maxim izes a particular objective function. Recently, it has been shown that some essential stoichiometric properties of glycolysis can be explained on the basis of the requirement for a high ATP production rate. Because the number of stoichiometrically feasible designs increases strongly with the number of reactions involved, a systematic analysis of all the possibilities turns out to be inaccessible beyond a certain system size. We present, therefore , an alternative approach to compute in a more efficient way the optimal de sign of glycolysis interacting with an external ATP-consuming reaction. The algorithm is based on the laws of evolution by natural selection, and may be viewed as a particular version of evolutionary algorithms. The following conclusions are derived: (a) evolutionary algorithms are very useful searc h strategies in determining optimal stoichiometries of metabolic pathways. (b) Essential topological features of the glycolytic network may be explain ed on the basis of flux optimization. (c) There is a strong interrelation b etween the optimal stoichiometries and the thermodynamic and kinetic proper ties of the participating reactions. (d) Some subsequences of reactions in optimal pathways are strongly conserved at variation of system parameters, which may be understood by applying principles of metabolic control analysi s. (C) 1999 Academic Press.