title: Optimal programs of pathway control: dissecting the influence of pathway topology and feedback inhibition on pathway regulation.
abstract: BACKGROUND
  Adjusting the capacity of metabolic pathways in response to rapidly changing environmental conditions is an important component of microbial adaptation strategies to stochastic environments. In this work, we use advanced dynamic optimization techniques combined with theoretical models to study which reactions in pathways are optimally targeted by regulatory interactions in order to minimize the regulatory effort that is required to adjust the flux through a complex metabolic network. Moreover, we analyze how constraints in the speed at which an organism can respond on a proteomic level influences these optimal targets of pathway control.
  
  
  RESULTS
  We find that limitations in protein biosynthetic rates have a strong influence. With increasing protein biosynthetic rates the regulatory effort targeting the initial enzyme in a pathway is reduced while the regulatory effort in the terminal enzyme is increased. Studying the impact of allosteric regulation for different pathway topologies, we find that the presence of feedback inhibition by products of metabolic pathways allows organisms to reduce the regulatory effort that is required to control a metabolic pathway in all cases. In a linear pathway this even leads to the case where the sole transcriptional regulatory control of the terminal enzyme is sufficient to control flux through the entire pathway. We confirm the utilization of these pathway regulation strategies through the large-scale analysis of transcriptional regulation in several hundred prokaryotes.
  
  
  CONCLUSIONS
  This work expands our knowledge about optimal programs of pathway control. Optimal targets of pathway control strongly depend on the speed at which proteins can be synthesized. Moreover, post-translational regulation such as allosteric regulation allows to strongly reduce the number of transcriptional regulatory interactions required to control a metabolic pathway across different pathway topologies.
authors.affiliation: Bioprocess Engineering Group, Spanish National Research Council, IIM-CSIC, C/Eduardo Cabello 6, Vigo, 36208, Spain. gundian@iim.csic.es.
authors.forename: Gundián M
authors.initials: GM
authors.lastname: de Hijas-Liste
authors.affiliation: Bioprocess Engineering Group, Spanish National Research Council, IIM-CSIC, C/Eduardo Cabello 6, Vigo, 36208, Spain. ebalsa@iim.csic.es.
authors.forename: Eva
authors.initials: E
authors.lastname: Balsa-Canto
authors.affiliation: esearch Group Theoretical Systems Biology, Friedrich Schiller University Jena, Leutragraben 1,, Jena, 07743, Germany. jan.ewald@uni-jena.de.
authors.forename: Jan
authors.initials: J
authors.lastname: Ewald
authors.affiliation: esearch Group Theoretical Systems Biology, Friedrich Schiller University Jena, Leutragraben 1,, Jena, 07743, Germany. ebalsa@iim.csic.es.
authors.forename: Martin
authors.initials: M
authors.lastname: Bartl
authors.affiliation: Simulation and Optimal Processes Group, Ilmenau University of Technology, P.O.Box 100565, Ilmenau, 98684, Germany. ebalsa@iim.csic.es.
authors.forename: Pu
authors.initials: P
authors.lastname: Li
authors.affiliation: Bioprocess Engineering Group, Spanish National Research Council, IIM-CSIC, C/Eduardo Cabello 6, Vigo, 36208, Spain. julio@iim.csic.es.
authors.forename: Julio R
authors.initials: JR
authors.lastname: Banga
authors.affiliation: esearch Group Theoretical Systems Biology, Friedrich Schiller University Jena, Leutragraben 1,, Jena, 07743, Germany. c.kaleta@iem.uni-kiel.de.|Research Group Medical Systems Biology, Christian-Albrechts-University Kiel, Brunswiker Straße 10, Kiel, 24105, Germany. c.kaleta@iem.uni-kiel.de.
authors.forename: Christoph
authors.initials: C
authors.lastname: Kaleta
mesh_terms: D000465:Algorithms; D000494:Allosteric Regulation; D019295:Computational Biology / Q000379:methods*; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D025461:Feedback, Physiological; D015964:Gene Expression Regulation, Bacterial; D053858:Metabolic Networks and Pathways; D008962:Models, Theoretical; D011506:Proteins / Q000378:metabolism*; D040901:Proteomics / Q000379:methods*
chemical_list: D011506:Proteins