(291a) Constructing Predictive Kinetic Models of Metabolism with Transcriptional Regulation
- Conference: AIChE Annual Meeting
- Year: 2017
- Proceeding: 2017 Annual Meeting
- Group: Food, Pharmaceutical & Bioengineering Division
- Time: Tuesday, October 31, 2017 - 8:00am-8:18am
Kinetic models simulate genetic perturbations by modifying specific enzyme levels a priori based on the mutant genotype information, which in turn modulates the concentrations of metabolites that the enzyme acts upon. However, the enzyme levels of an organism are also regulated by the available transcriptional machinery (global regulation) as well as by the changes in concentration levels of regulatory metabolites (specific regulation) under any given genetic or environmental perturbation. Thus, we expand the scope of the developed kinetic models by incorporating transcriptional regulatory layer which refines enzyme levels based on a linear combination of log-normalized changes in growth rate (global) and select intracellular metabolite pool (specific) levels. We use transcriptomic datasets that provide genome-wide collections of mRNA levels under genetic and environmental perturbations to estimate the transcriptional regulatory model parameters and validate their statistical significance. The developed transcriptional regulatory model captures the impact of perturbations in key metabolite pools on transcript levels of 85 enzymes spanning glycolysis, amino acid and nucleotide metabolism pathways. Ultimately, the transcriptional regulation integrated kinetic model captures the impact of enzyme level changes on metabolite concentrations as well as the regulation of enzyme levels by metabolite concentration changes increasing prediction fidelity.
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