Publications

Abstract (Expand)

Understanding optimality principles shaping the evolution of regulatory networks controlling metabolism is crucial for deriving a holistic picture of how metabolism is integrated into key cellular processes such as growth, adaptation and pathogenicity. While in the past the focus of research in pathway regulation was mainly based on stationary states, more recently dynamic optimization has proved to be an ideal tool to decipher regulatory strategies for metabolic pathways in response to environmental cues. In this short review, we summarize recent advances in the elucidation of optimal regulatory strategies and identification of optimal control points in metabolic pathways. We discuss biological implications of the discovered optimality principles on genome organization and provide examples how the derived knowledge can be used to identify new treatment strategies against pathogens. Furthermore, we briefly discuss the variety of approaches for solving dynamic optimization problems and emphasize whole-cell resource allocation models as an important emerging area of research that will allow us to study the regulation of metabolism on the whole-cell level.

Authors: Jan Ewald, M. Bartl, Christoph Kaleta

Date Published: 30th Jul 2017

Journal: Biochem Soc Trans

Abstract (Expand)

A precise and rapid adjustment of fluxes through metabolic pathways is crucial for organisms to prevail in changing environmental conditions. Based on this reasoning, many guiding principles that govern the evolution of metabolic networks and their regulation have been uncovered. To this end, methods from dynamic optimization are ideally suited since they allow to uncover optimality principles behind the regulation of metabolic networks. We used dynamic optimization to investigate the influence of toxic intermediates in connection with the efficiency of enzymes on the regulation of a linear metabolic pathway. Our results predict that transcriptional regulation favors the control of highly efficient enzymes with less toxic upstream intermediates to reduce accumulation of toxic downstream intermediates. We show that the derived optimality principles hold by the analysis of the interplay between intermediate toxicity and pathway regulation in the metabolic pathways of over 5000 sequenced prokaryotes. Moreover, using the lipopolysaccharide biosynthesis in Escherichia coli as an example, we show how knowledge about the relation of regulation, kinetic efficiency and intermediate toxicity can be used to identify drug targets, which control endogenous toxic metabolites and prevent microbial growth. Beyond prokaryotes, we discuss the potential of our findings for the development of antifungal drugs.

Authors: Jan Ewald, M. Bartl, Thomas Dandekar, Christoph Kaleta

Date Published: 18th Feb 2017

Journal: PLoS Comput Biol

Abstract (Expand)

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: G. M. de Hijas-Liste, E. Balsa-Canto, Jan Ewald, M. Bartl, P. Li, J. R. Banga, Christoph Kaleta

Date Published: 16th May 2015

Journal: BMC Bioinformatics

Abstract (Expand)

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: G. M. de Hijas-Liste, E. Balsa-Canto, J. Ewald, M. Bartl, P. Li, J. R. Banga, Christoph Kaleta

Date Published: 16th May 2015

Journal: BMC Bioinformatics

Abstract (Expand)

In this work, we investigate optimality principles behind synthesis strategies for protein complexes using a dynamic optimization approach. We show that the cellular capacity of protein synthesis has a strong influence on optimal synthesis strategies reaching from a simultaneous to a sequential synthesis of the subunits of a protein complex. Sequential synthesis is preferred if protein synthesis is strongly limited, whereas a simultaneous synthesis is optimal in situations with a high protein synthesis capacity. We confirm the predictions of our optimization approach through the analysis of the operonic organization of protein complexes in several hundred prokaryotes. Thereby, we are able to show that cellular protein synthesis capacity is a driving force in the dissolution of operons comprising the subunits of a protein complex. Thus, we also provide a tested hypothesis explaining why the subunits of many prokaryotic protein complexes are distributed across several operons despite the presumably less precise co-regulation.

Authors: Jan Ewald, M. Kotzing, M. Bartl, Christoph Kaleta

Date Published: 1st May 2015

Journal: Metabolites

Abstract (Expand)

In this work, we investigate optimality principles behind synthesis strategies for protein complexes using a dynamic optimization approach. We show that the cellular capacity of protein synthesis has a strong influence on optimal synthesis strategies reaching from a simultaneous to a sequential synthesis of the subunits of a protein complex. Sequential synthesis is preferred if protein synthesis is strongly limited, whereas a simultaneous synthesis is optimal in situations with a high protein synthesis capacity. We confirm the predictions of our optimization approach through the analysis of the operonic organization of protein complexes in several hundred prokaryotes. Thereby, we are able to show that cellular protein synthesis capacity is a driving force in the dissolution of operons comprising the subunits of a protein complex. Thus, we also provide a tested hypothesis explaining why the subunits of many prokaryotic protein complexes are distributed across several operons despite the presumably less precise co-regulation.

Authors: J. Ewald, M. Kotzing, M. Bartl, Christoph Kaleta

Date Published: 1st May 2015

Journal: Metabolites

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