An exact arithmetic toolbox for a consistent and reproducible structural analysis of metabolic network models

Abstract

Constraint-based models are currently the only methodology that allows the study of metabolism at the whole-genome scale. Flux balance analysis is commonly used to analyse constraint-based models. Curiously, the results of this analysis vary with the software being run, a situation that we show can be remedied by using exact rather than floating-point arithmetic. Here we introduce MONGOOSE, a toolbox for analysing the structure of constraint-based metabolic models in exact arithmetic. We apply MONGOOSE to the analysis of 98 existing metabolic network models and find that the biomass reaction is surprisingly blocked (unable to sustain non-zero flux) in nearly half of them. We propose a principled approach for unblocking these reactions and extend it to the problems of identifying essential and synthetic lethal reactions and minimal media. Our structural insights enable a systematic study of constraint-based metabolic models, yielding a deeper understanding of their possibilities and limitations.

Figure 1. Flowchart of the MONGOOSE pipeline.

A schematic representation of the interaction between different parts of the MONGOOSE pipeline.

Figure 2. Comparison of CPLEX and MONGOOSE.

MONGOOSE identifies all reaction pairs that are in an enzyme subset for these eight metabolic networks. The reaction pairs detected as being in an enzyme subset by CPLEX are shown in blue, while those not detected as such are shown in red.