title: A rheostat mechanism governs the bifurcation of carbon flux in mycobacteria.
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.
authors.affiliation: School of Life Sciences, Swiss Federal Institute of Technology in Lausanne (EPFL), CH-1015 Lausanne, Switzerland.
authors.forename: Paul
authors.initials: P
authors.lastname: Murima
authors.affiliation: Institute of Molecular Systems Biology, Swiss Federal Institute of Technology in Zürich (ETHZ), CH-8093 Zürich, Switzerland.
authors.forename: Michael
authors.identifier: 0000-0002-5797-3589
authors.initials: M
authors.lastname: Zimmermann
authors.affiliation: School of Life Sciences, Swiss Federal Institute of Technology in Lausanne (EPFL), CH-1015 Lausanne, Switzerland.
authors.forename: Tarun
authors.initials: T
authors.lastname: Chopra
authors.affiliation: Protein Crystallography Platform, Swiss Federal Institute of Technology in Lausanne (EPFL), CH-1015 Lausanne, Switzerland.
authors.forename: Florence
authors.initials: F
authors.lastname: Pojer
authors.affiliation: School of Life Sciences, Swiss Federal Institute of Technology in Lausanne (EPFL), CH-1015 Lausanne, Switzerland.
authors.forename: Giulia
authors.initials: G
authors.lastname: Fonti
authors.affiliation: School of Life Sciences, Swiss Federal Institute of Technology in Lausanne (EPFL), CH-1015 Lausanne, Switzerland.
authors.forename: Matteo
authors.initials: M
authors.lastname: Dal Peraro
authors.affiliation: Department of Microbiology, Yong Loo Lin School of Medicine and Immunology Programme, Life Sciences Institute, National University of Singapore, Singapore 117456, Singapore.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Alonso
authors.affiliation: Institute of Molecular Systems Biology, Swiss Federal Institute of Technology in Zürich (ETHZ), CH-8093 Zürich, Switzerland.
authors.forename: Uwe
authors.initials: U
authors.lastname: Sauer
authors.affiliation: Lee Kong Chian School of Medicine and School of Biological Sciences, Nanyang Technological University, 59 Nanyang Drive, Singapore 636 921, Singapore.
authors.forename: Kevin
authors.initials: K
authors.lastname: Pethe
authors.affiliation: School of Life Sciences, Swiss Federal Institute of Technology in Lausanne (EPFL), CH-1015 Lausanne, Switzerland.
authors.forename: John D
authors.initials: JD
authors.lastname: McKinney
mesh_terms: D001426:Bacterial Proteins / Q000378:metabolism; D002244:Carbon / Q000378:metabolism*; D057486:Carbon Cycle; D002952:Citric Acid Cycle; D005227:Fatty Acids / Q000378:metabolism*; D006038:Glyoxylates / Q000378:metabolism; D007521:Isocitrate Dehydrogenase / Q000378:metabolism; D007522:Isocitrate Lyase / Q000378:metabolism; D007700:Kinetics; D008954:Models, Biological; D009161:Mycobacterium / Q000145:classification / Q000378:metabolism*; D013045:Species Specificity
chemical_list: D001426:Bacterial Proteins; D005227:Fatty Acids; D006038:Glyoxylates; D002244:Carbon; D007521:Isocitrate Dehydrogenase; D007522:Isocitrate Lyase; C031150:glyoxylic acid