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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.

SEEK ID: https://funginet.hki-jena.de/models/18?version=1

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Organism: Not specified

Model type: Ordinary differential equations (ODE)

Model format: Matlab package

Execution or visualisation environment: Not specified

Model image: (Click on the image to zoom)

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Views: 1366   Downloads: 442

Created: 24th Aug 2017 at 08:34

Last used: 31st Jul 2021 at 17:21

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Related items

B2

Interaction networks of signalling molecules and pathways between the pathogenic fungi Aspergillus fumigatus and Candida albicans and their human host

Programme: Collaborative Research Center / Transregio 124 "Pathogenic fungi and their human host: Networks of Interaction - FungiNet"

Public web page: http://www.funginet.de/project-b2.html

Optimality principles reveal a complex interplay of intermediate toxicity and kinetic efficiency in the regulation of prokaryotic metabolism.
B2

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

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