Ensemble modeling for aromatic production in Escherichia coli.
Ensemble Modeling (EM) is a recently developed method for metabolic modeling, particularly for utilizing the effect of enzyme tuning data on the production of a specific compound to refine the model. This approach is used here to investigate the production of aromatic products in Escherichia coli. Instead of using dynamic metabolite data to fit a model, the EM approach uses phenotypic data (effects of enzyme overexpression or knockouts on the steady state production rate) to screen possible models. These data are routinely generated during strain design. An ensemble of models is constructed that all reach the same steady state and are based on the same mechanistic framework at the elementary reaction level. The behavior of the models spans the kinetics allowable by thermodynamics. Then by using existing data from the literature for the overexpression of genes coding for transketolase (Tkt), transaldolase (Tal), and phosphoenolpyruvate synthase (Pps) to screen the ensemble, we arrive at a set of models that properly describes the known enzyme overexpression phenotypes. This subset of models becomes more predictive as additional data are used to refine the models. The final ensemble of models demonstrates the characteristic of the cell that Tkt is the first rate controlling step, and correctly predicts that only after Tkt is overexpressed does an increase in Pps increase the production rate of aromatics. This work demonstrates that EM is able to capture the result of enzyme overexpression on aromatic producing bacteria by successfully utilizing routinely generated enzyme tuning data to guide model learning.
Rizk
Matthew L
ML
Department of Chemical and Biomolecular Engineering, University of California Los Angeles, Los Angeles, California, United States of America.
Liao
James C
JC
D024322:Amino Acids, Aromatic / Q000737:chemistry; D019295:Computational Biology / Q000379:methods; D003198:Computer Simulation; D004926:Escherichia coli / Q000235:genetics* / Q000378:metabolism; D015964:Gene Expression Regulation, Bacterial; D007700:Kinetics; D008957:Models, Genetic; D015233:Models, Statistical; D008962:Models, Theoretical; D010641:Phenotype; D017866:Phosphotransferases (Paired Acceptors) / Q000235:genetics; D025941:Protein Interaction Mapping; D013816:Thermodynamics; D014153:Transaldolase / Q000235:genetics; D014174:Transketolase / Q000235:genetics
D024322:Amino Acids, Aromatic; D014174:Transketolase; D014153:Transaldolase; D017866:Phosphotransferases (Paired Acceptors); C022509:pyruvate, water dikinase