Phenotype-specific estimation of metabolic fluxes using gene expression data

A cell’s genome influences its metabolism via the expression of enzyme-related genes, but transcriptome and fluxome are not perfectly correlated as post-transcriptional mechanisms also regulate reaction’s kinetics. Here, we addressed the question: given a transcriptome, how unobserved mechanisms of reaction kinetics should be systematically accounted for when inferring the fluxome? To infer the most likely and least biased fluxome, we present Pheflux, a constraint-based model maximizing Shannon’s entropy of fluxes per mRNA. Benchmarked against (13)C fluxes of yeast and bacteria, Pheflux accurately estimates the carbon core metabolism. We applied Pheflux to thousands of normal and tumor cell transcriptomes obtained from The Cancer Genome Atlas. Pheflux showed statistically significantly higher glucose yields on lactate in breast, kidney, and bronchus-lung tumoral cells than their normal counterparts. Results are consistent with the Warburg effect, a hallmark of cancer metabolism, suggesting that Pheflux can be efficiently used to study the metabolism of eukaryotic cells.