An algorithm for the reduction of genome-scale metabolic network models to meaningful core models

Constraint-based analysis of genome-scale metabolic models has become a key methodology to gain insights into functions, capabilities, and properties of cellular metabolism. Since their inception, the size and complexity of genome-scale metabolic reconstructions has significantly increased, with a concomitant increase in computational effort required for their analysis. Many stoichiometric methods cannot be applied to large networks comprising several thousand reactions. Furthermore, basic principles of an organism's metabolism can sometimes be easier studied in smaller models focusing on central metabolism. Therefore, an automated and unbiased reduction procedure delivering meaningful core networks from well-curated genome-scale reconstructions is highly desirable.

Here we present NetworkReducer, a new algorithm for an automated reduction of metabolic reconstructions to obtain smaller models capturing the central metabolism or other metabolic modules of interest. The algorithm takes as input a network model and a list of protected elements and functions (phenotypes) and applies a pruning step followed by an optional compression step. Network pruning removes elements of the network that are dispensable for the protected functions and delivers a subnetwork of the full system. Loss-free network compression further reduces the network size but not the complexity (dimension) of the solution space. As a proof of concept, we applied NetworkReducer to the iAF1260 genome-scale model of Escherichia coli (2384 reactions, 1669 internal metabolites) to obtain a reduced model that (i) allows the same maximal growth rates under aerobic and anaerobic conditions as in the full model, and (ii) preserves a protected set of reactions representing the central carbon metabolism. The reduced representation comprises 85 metabolites and 105 reactions which we compare to a manually derived E. coli core model. As one particular strength of our approach, NetworkReducer derives a condensed biomass synthesis reaction that is consistent with the full genome-scale model. In a second case study, we reduced a genome-scale model of the cyanobacterium Synechocystis sp. PCC 6803 to obtain a small metabolic module comprising photosynthetic core reactions and the Calvin-Benson cycle allowing synthesis of both biomass and a biofuel (ethanol).

Although only genome-scale models provide a complete description of an organism's metabolic capabilities, an unbiased stoichiometric reduction of large-scale metabolic models is highly useful. We are confident that the NetworkReducer algorithm provides a valuable tool for the application of computationally expensive analyses, for educational purposes, as well to identify core models for kinetic modeling and isotopic tracer experiments.