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A rheostat mechanism governs the bifurcation of carbon flux in mycobacteria

Fatty acid metabolism is an important feature of the pathogenicity of Mycobacterium tuberculosis during infection. Consumption of fatty acids requires regulation of carbon flux bifurcation between the oxidative TCA cycle and the glyoxylate shunt. In Escherichia coli, flux bifurcation is regulated by...

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Autores principales: Murima, Paul, Zimmermann, Michael, Chopra, Tarun, Pojer, Florence, Fonti, Giulia, Dal Peraro, Matteo, Alonso, Sylvie, Sauer, Uwe, Pethe, Kevin, McKinney, John D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4999502/
https://www.ncbi.nlm.nih.gov/pubmed/27555519
http://dx.doi.org/10.1038/ncomms12527
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author Murima, Paul
Zimmermann, Michael
Chopra, Tarun
Pojer, Florence
Fonti, Giulia
Dal Peraro, Matteo
Alonso, Sylvie
Sauer, Uwe
Pethe, Kevin
McKinney, John D.
author_facet Murima, Paul
Zimmermann, Michael
Chopra, Tarun
Pojer, Florence
Fonti, Giulia
Dal Peraro, Matteo
Alonso, Sylvie
Sauer, Uwe
Pethe, Kevin
McKinney, John D.
author_sort Murima, Paul
collection PubMed
description Fatty acid metabolism is an important feature of the pathogenicity of Mycobacterium tuberculosis during infection. Consumption of fatty acids requires regulation of carbon flux bifurcation between the oxidative TCA cycle and the glyoxylate shunt. In Escherichia coli, flux bifurcation is regulated by phosphorylation-mediated inhibition of isocitrate dehydrogenase (ICD), a paradigmatic example of post-translational mechanisms governing metabolic fluxes. Here, we demonstrate that, in contrast to E. coli, carbon flux bifurcation in mycobacteria is regulated not by phosphorylation but through metabolic cross-activation of ICD by glyoxylate, which is produced by the glyoxylate shunt enzyme isocitrate lyase (ICL). This regulatory circuit maintains stable partitioning of fluxes, thus ensuring a balance between anaplerosis, energy production, and precursor biosynthesis. The rheostat-like mechanism of metabolite-mediated control of flux partitioning demonstrates the importance of allosteric regulation during metabolic steady-state. The sensitivity of this regulatory mechanism to perturbations presents a potentially attractive target for chemotherapy.
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spelling pubmed-49995022016-09-08 A rheostat mechanism governs the bifurcation of carbon flux in mycobacteria Murima, Paul Zimmermann, Michael Chopra, Tarun Pojer, Florence Fonti, Giulia Dal Peraro, Matteo Alonso, Sylvie Sauer, Uwe Pethe, Kevin McKinney, John D. Nat Commun Article Fatty acid metabolism is an important feature of the pathogenicity of Mycobacterium tuberculosis during infection. Consumption of fatty acids requires regulation of carbon flux bifurcation between the oxidative TCA cycle and the glyoxylate shunt. In Escherichia coli, flux bifurcation is regulated by phosphorylation-mediated inhibition of isocitrate dehydrogenase (ICD), a paradigmatic example of post-translational mechanisms governing metabolic fluxes. Here, we demonstrate that, in contrast to E. coli, carbon flux bifurcation in mycobacteria is regulated not by phosphorylation but through metabolic cross-activation of ICD by glyoxylate, which is produced by the glyoxylate shunt enzyme isocitrate lyase (ICL). This regulatory circuit maintains stable partitioning of fluxes, thus ensuring a balance between anaplerosis, energy production, and precursor biosynthesis. The rheostat-like mechanism of metabolite-mediated control of flux partitioning demonstrates the importance of allosteric regulation during metabolic steady-state. The sensitivity of this regulatory mechanism to perturbations presents a potentially attractive target for chemotherapy. Nature Publishing Group 2016-08-24 /pmc/articles/PMC4999502/ /pubmed/27555519 http://dx.doi.org/10.1038/ncomms12527 Text en Copyright © 2016, The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Murima, Paul
Zimmermann, Michael
Chopra, Tarun
Pojer, Florence
Fonti, Giulia
Dal Peraro, Matteo
Alonso, Sylvie
Sauer, Uwe
Pethe, Kevin
McKinney, John D.
A rheostat mechanism governs the bifurcation of carbon flux in mycobacteria
title A rheostat mechanism governs the bifurcation of carbon flux in mycobacteria
title_full A rheostat mechanism governs the bifurcation of carbon flux in mycobacteria
title_fullStr A rheostat mechanism governs the bifurcation of carbon flux in mycobacteria
title_full_unstemmed A rheostat mechanism governs the bifurcation of carbon flux in mycobacteria
title_short A rheostat mechanism governs the bifurcation of carbon flux in mycobacteria
title_sort rheostat mechanism governs the bifurcation of carbon flux in mycobacteria
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4999502/
https://www.ncbi.nlm.nih.gov/pubmed/27555519
http://dx.doi.org/10.1038/ncomms12527
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