A rheostat mechanism governs the bifurcation of carbon flux in mycobacteria

Paul Murima (), Michael Zimmermann, Tarun Chopra, Florence Pojer, Giulia Fonti, Matteo Dal Peraro, Sylvie Alonso, Uwe Sauer, Kevin Pethe () and John D. McKinney ()
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Paul Murima: School of Life Sciences, Swiss Federal Institute of Technology in Lausanne (EPFL)
Michael Zimmermann: Institute of Molecular Systems Biology, Swiss Federal Institute of Technology in Zürich (ETHZ)
Tarun Chopra: School of Life Sciences, Swiss Federal Institute of Technology in Lausanne (EPFL)
Florence Pojer: Protein Crystallography Platform, Swiss Federal Institute of Technology in Lausanne (EPFL)
Giulia Fonti: School of Life Sciences, Swiss Federal Institute of Technology in Lausanne (EPFL)
Matteo Dal Peraro: School of Life Sciences, Swiss Federal Institute of Technology in Lausanne (EPFL)
Sylvie Alonso: Yong Loo Lin School of Medicine and Immunology Programme, Life Sciences Institute, National University of Singapore
Uwe Sauer: Institute of Molecular Systems Biology, Swiss Federal Institute of Technology in Zürich (ETHZ)
Kevin Pethe: Lee Kong Chian School of Medicine and School of Biological Sciences, Nanyang Technological University
John D. McKinney: School of Life Sciences, Swiss Federal Institute of Technology in Lausanne (EPFL)

Nature Communications, 2016, vol. 7, issue 1, 1-13

Abstract: Abstract 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.

Date: 2016
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DOI: 10.1038/ncomms12527

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