title: Integrated, systems metabolic picture of acetone-butanol-ethanol fermentation by Clostridium acetobutylicum.
abstract: Microbial metabolism involves complex, system-level processes implemented via the orchestration of metabolic reactions, gene regulation, and environmental cues. One canonical example of such processes is acetone-butanol-ethanol (ABE) fermentation by Clostridium acetobutylicum, during which cells convert carbon sources to organic acids that are later reassimilated to produce solvents as a strategy for cellular survival. The complexity and systems nature of the process have been largely underappreciated, rendering challenges in understanding and optimizing solvent production. Here, we present a system-level computational framework for ABE fermentation that combines metabolic reactions, gene regulation, and environmental cues. We developed the framework by decomposing the entire system into three modules, building each module separately, and then assembling them back into an integrated system. During the model construction, a bottom-up approach was used to link molecular events at the single-cell level into the events at the population level. The integrated model was able to successfully reproduce ABE fermentations of the WT C. acetobutylicum (ATCC 824), as well as its mutants, using data obtained from our own experiments and from literature. Furthermore, the model confers successful predictions of the fermentations with various network perturbations across metabolic, genetic, and environmental aspects. From foundation to applications, the framework advances our understanding of complex clostridial metabolism and physiology and also facilitates the development of systems engineering strategies for the production of advanced biofuels.
authors.affiliation: Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801; Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801;
authors.forename: Chen
authors.initials: C
authors.lastname: Liao
authors.affiliation: Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801; Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, Urbana, IL 61801;
authors.forename: Seung-Oh
authors.initials: SO
authors.lastname: Seo
authors.affiliation: Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801; Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801; Department of Bioengineering, Faculty of Engineering, University of Firat, 23119 Elazig, Turkey;
authors.forename: Venhar
authors.initials: V
authors.lastname: Celik
authors.affiliation: Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801; Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801;
authors.forename: Huaiwei
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801; Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801;
authors.forename: Wentao
authors.initials: W
authors.lastname: Kong
authors.affiliation: Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, Urbana, IL 61801;
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, Urbana, IL 61801; Integrated Bioprocessing Research Laboratory, University of Illinois at Urbana-Champaign, Urbana, IL 61801;
authors.forename: Hans
authors.initials: H
authors.lastname: Blaschek
authors.affiliation: Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801; Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, Urbana, IL 61801; Energy Bioscience Institute, University of Illinois at Urbana-Champaign, Urbana, IL 61801;
authors.forename: Yong-Su
authors.initials: YS
authors.lastname: Jin
authors.affiliation: Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801; Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801; Department of Physics, University of Illinois at Urbana-Champaign, Urbana, IL 61801 luting@illinois.edu.
authors.forename: Ting
authors.initials: T
authors.lastname: Lu
mesh_terms: D000096:Acetone / Q000378:metabolism*; D000465:Algorithms; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D056804:Biofuels; D000440:Butanols / Q000378:metabolism*; D046969:Clostridium acetobutylicum / Q000235:genetics / Q000378:metabolism*; D003198:Computer Simulation; D000431:Ethanol / Q000378:metabolism*; D005285:Fermentation; D015964:Gene Expression Regulation, Bacterial; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008954:Models, Biological
chemical_list: D001426:Bacterial Proteins; D056804:Biofuels; D000440:Butanols; D000096:Acetone; D000431:Ethanol
keywords: ABE fermentation; clostridial physiology; integrated modeling; metabolic engineering; systems biology