Influence of toxic intermediates on optimal metabolic pathway regulation
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Dynamic optimization model to study control points in metabolic pathways to identify general strategies behind pathway regulation.
Toxic intermediates determine which enzyme control pathway flux and prevent their accumulation.
Therefore those enzymes are drug targets since deregulation leads to self-poisoning of pathogens.

Creator: Jan Ewald

Contributor: Jan Ewald

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Deciphering the regulation of metabolism with dynamic optimization: an overview of recent advances.
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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

Optimality principles reveal a complex interplay of intermediate toxicity and kinetic efficiency in the regulation of prokaryotic metabolism.
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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

Dynamic optimization of pathway regulation and intermediate toxicity prediction to elucidate drug targets in pathogenic fungi
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Invited talk at Workshop for 'Dynamics, Thermodynamics, and Information Processing in Chemical Networks' of Luxembourg University (15.06.2017)

Creator: Jan Ewald

Contributor: Jan Ewald

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