Designing metabolism: Alternative connectivities for the pentose phosphate pathway

Abstract

We present a method for generating alternative biochemical pathways between specified compounds. We systematically generated diverse alternatives to the nonoxidative stage of the pentose phosphate pathway, by first finding pathways between 5-carbon and 6-carbon skeletons. Each solution of the equations for the stoichiometric coefficients of skeleton-changing reactions defines a set of networks. Within each set we selected networks with modules; a module is a coupled set of reactions that occurs more than one in a network. The networks can be classified into at least 53 families in at least seven superfamilies, according to the number, the input-output relations, and the internal structure of their modules. We then assigned classes of enzymes to mediate transformations of carbon skeletons and modifications of functional groups. The ensemble of candidate networks was too large to allow complete determination of the optimal network. However, among the networks we studied the real pathway is especially favorable in several respects. It has few steps, uses no reducing or oxidizing compounds, requires only one ATP in one direction of flux, and does not depend on recurrent inputs.