Optimization of Metabolism: The Evolution of Metabolic Pathways Toward Simplicity Through the Game of the Pentose Phosphate Cycle

Previous theoretical studies on the pentose phosphate cycle (Meléndez-Hevia et al., 1985, 1988, 1990) demonstrated that simplicity in metabolism, defined as the least possible number of enzyme reactions in a pathway, has been a target in biological evolution. Those results demonstrated that a process of optimization has occurred in the evolution of metabolism. However, the results also suggest a number of questions of general interest: (i) Why simplicity? What is the selective advantage of simplicity in metabolic pathways? (ii) How has simplicity been achieved? Can natural selection mechanisms solve the problems of combinatorial optimization in the design of metabolism? (iii) Are the reaction mechanisms of the pentose phosphate cycle (transketolase and transaldolase) the best suited for pentose-hexose interconversion? For example, could a simpler pathway be possible if other enzymes (e.g. one carbon transfer) were to exist? In this paper we analyze all these questions and present results which demonstrate that: (i) Simplicity (the least possible number of steps) in a metabolic pathway is a feature which supplies more catalytic efficiency. That is, for a given metabolic conversion, a short pathway yields more flux than a long one. (ii) Natural selection working at molecular level accounts for the selection of the shortest pathway. (iii) It is not possible to find any other set of enzyme mechanisms capable of producing a simpler solution for the pentose phosphate pathway; any other mechanism, such as one carbon transfer between sugars, leads to a more complicated solution. Therefore, our results demonstrate that both the design of this pathway and the enzyme mechanisms themselves have been optimized.