06/07/2013
Emerging Discipline of Structural Systems Biology Reveals E. coli Heat Tolerance
Cellular thermosensitivity depends on proteome stability.
The Science
Microbial sensitivity to heat, or thermosensitivity, depends on the stability of cellular proteins and their ability to remain in an active, folded state. Research to improve microbial survival and function at higher temperatures has mainly focused on strategies for increasing the structural stability of individual proteins. A new approach called structural systems biology directly assesses the genome-scale metabolic potential of a model organism, E. coli, for thermostability. Using this approach, metabolic reactions of E. coli were integrated with three-dimensional structures of each catalytic enzyme. To simulate E. coli growth at various temperatures, protein (structural) activity functions were defined to impose temperature constraints on the metabolic models. This combined metabolic-structural method allows researchers to integrate temperature-dependent information about enzyme function with simulations of microbial metabolic growth. This approach enabled simulation of E. coli growth under various temperature conditions that was in good agreement with experimental growth data. It also provided mechanistic interpretations of mutations that conferred greater thermostability in E. coli. This new approach has important implications for developing industrial microbes as biocatalysts.
Summary
Genome-scale network reconstruction has enabled predictive modeling of metabolism for many systems. Traditionally, protein structural information has not been represented in such reconstructions. Expansion of a genome-scale model of Escherichia coli metabolism by including experimental and predicted protein structures enabled the analysis of protein thermostability in a network context. This analysis allowed the prediction of protein activities that limit network function at superoptimal temperatures and mechanistic interpretations of mutations found in strains adapted to heat. Predicted growth-limiting factors for thermotolerance were validated through nutrient supplementation experiments and defined metabolic sensitivities to heat stress, providing evidence that metabolic enzyme thermostability is rate-limiting at superoptimal temperatures. Inclusion of structural information expanded the content and predictive capability of genome-scale metabolic networks that enable structural systems biology of metabolism.
Principal Investigator
Bernhard O. Palsson
University of California–San Diego
References
Chang, R. L., K. Andrews, D. Kim, Z. Li, A. Godzik, and B. O. Palsson. 2013. “Structural Systems Biology Evaluation of Metabolic Thermotolerance in Escherichia coli,” Science 340, 1220–23. DOI:10.1126/science/1234012.