关键词:
Engineering
Bioinformatics
Computer science
Genetics
Physics
摘要:
Clostridia organisms have a unique diversity in substrate utilization and metabolism that include CO2 fixation, lignocellulose consumption, and both acetogenic and solventogenic regimes that makes them useful as production platforms for a wide range of chemicals. Unlike model organisms, however the mechanistic determinants of phenotype are not well understood, presenting a challenge to their engineering and development for use in industrial fermentation processes. Kinetic models of metabolism are promising tools for studying Clostridia because they offer a means for not only predicting metabolic state in response to network perturbations, but also for elucidating mechanisms actively controlling metabolism. They are advantageous over purely stoichiometric models for these purposes because they capture the simultaneous and interrelated shift in metabolite concentration and metabolic flux in response to network perturbations. In Chapter 1, we present an overview of recent advances in the development of kinetic models of metabolism for application towards metabolic engineering. The ways in which key considerations made during network construction, formalism selection, and data curation steps influence predictive capability are first discussed. We then explore how accelerating kinetic parameterization can improve kinetic model applicability within design-build-test-learn cycles and expand the types of follow-up analysis that can be performed using large-scale kinetic models of metabolism. Finally, we explore how we can infer design targets through sensitivity analysis and provide an overview of the kinetic models that have been recently parameterized and deployed to aid in the rational design of microorganisms. Several hurdles to large-scale kinetic model parameterization exist, including data availability, computational expense, a lack of established best practices for parameterization and follow-up analysis. Although these challenges have been long recognized, a formal