Accurate prediction of flux distributions compatible with metabolite concentration effects in genome-scale metabolic...

Intracellular fluxes shape all cellular functions, and understanding how they are shaped by the joint effects of enzyme abundances and metabolite concentrations in vivo currently requires gathering matched quantitative proteomic and metabolomic data sets from resource-intensive experiments. Here, we present KineFlux, a hybrid approach that combines machine learning with enzyme-constrained metabolic models to accurately predict steady-state flux distributions using only quantitative proteomic data. KineFlux builds machine learning models for metabolite concentration effects on reaction fluxes, obtained by using fluxomics and proteomics data from a training set of experiments. Using fluxomic and proteomic data sets of Escherichia coli and Saccharomyces cerevisiae, we show that the steady-state flux distributions predicted by KineFlux are in line with fluxes estimated by classical approaches. We also demonstrate that the machine learning models embedded in KineFlux are transferrable at marginal loss of accuracy using independent testing data from E. coli. Therefore, KineFlux expands the usability of enzyme-constrained models towards accurate prediction of genome-scale flux distributions compatible with metabolite concentration effects without knowledge of enzyme kinetics.