Metabolic modeling predicts metabolite changes in Mycobacterium tuberculosis

Mycobacterium tuberculosis (MTB) is the causal agent of the disease tuberculosis (TB). Metabolic adaptations are thought to be critical to the survival of MTB during pathogenesis. Computational tools that can be used to study MTB metabolism in silico and prioritize resource-intensive experimental work could significantly accelerate research.

We have developed E-Flux-MFC, an enhancement of our original E-Flux method that enables the prediction of changes in the production of external and internal metabolites corresponding to gene expression measurements. We have used this method to simulate the changes in the metabolic state of Mycobacterium tuberculosis (MTB). We have validated the accuracy of E-Flux-MFC for predicting changes in lipids and metabolites during a hypoxia time course using previously published metabolomics and transcriptomics data. We have further validated the accuracy of the method for predicting changes in MTB lipids following the deletion and induction of two well-studied transcription factors (TFs). We have applied the method to predict the metabolic impact of the induction of each of the approximately 180 MTB TFs using a previously generated and publically available expression data set.

E-flux-MFC can be used to study global changes in MTB metabolites from gene expression data associated with environmental and genetic perturbations. The application of this method to a data set of MTB TF perturbations provides a resource for studying the large number of TFs whose functions remain unknown. Most TFs impact metabolites indirectly through the propagation of gene expression changes through the regulatory network rather than through their direct regulons. E-Flux-MFC is also applicable to any organism for which accurate metabolic models are available.