A Rheostat Mechanism Governs the Bifurcation of Carbon Flux in Mycobacteria

Overview

Journal Nat Commun

Specialty Biology

Date 2016 Aug 25

PMID 27555519

Citations 17

Authors

Paul Murima

Michael Zimmermann

Tarun Chopra

Florence Pojer

Giulia Fonti

Matteo Dal Peraro

Sylvie Alonso

Uwe Sauer

Kevin Pethe

John D McKinney

Affiliations

Soon will be listed here.

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.

Citing Articles

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