Theory for the systemic definition of metabolic pathways and their use in interpreting metabolic function from? A pathway-oriented perspective

Cellular metabolism is most often described and interpreted in terms of the biochemical reactions that make up the metabolic network. Genomics is prov iding near complete information regarding the genes/gene products participa ting in cellular metabolism for a growing number of organisms. As the true functional units of metabolic systems are its pathways, the time has arrive d to define metabolic pathways in the context of whole-eel metabolism for t he analysis of the structural design and capabilities of the metabolic netw ork. In this study, we present the theoretical foundations for the identifi cation of the unique set of systemically independent biochemical pathways, termed extreme pathways, based on system stochiometry and limited thermodyn amics. These pathways represent the edges of the steady-state flux cone der ived from convex analysis, and they can be used to represent any flux distr ibution achievable by the metabolic network. An algorithm is presented to d etermine the set of extreme pathways for a system of any complexity and a c lassification scheme is introduced for the characterization of these pathwa ys. The property of systemic independence is discussed along with its impli cations for issues related to metabolic regulation and the evolution of cel lular metabolic networks. The underlying pathway structure that is determin ed from the set of extreme pathways now provides us with the ability to ana lyse, interpret, and perhaps predict metabolic function from a pathway-base d perspective in addition to the traditional reaction-based perspective. Th e algorithm and classification scheme developed can be used to describe the pathway structure in annotated genomes to explore the capabilities of an o rganism. (C) 2000 Academic Press.