Feast: Choking on Acetyl-CoA, the Glyoxylate Shunt, and Acetyl-CoA-Driven Metabolism
Acetyl coenzyme A (acetyl-CoA) is an essential cofactor in central metabolism: the molecule is the entry point to the tricarboxylic acid (TCA) cycle that generates biomass, energy, and intermediates for macromolecules. Its importance is not limited to biosynthetic pathways: the oxidation of carbohydrates (via pyruvate), fatty acids (by the β-oxidation cycle), or aromatics (by various pathways) all produce acetyl-CoA as an end point of catabolism. Acetyl-CoA is also produced by the direct assimilation of acetate. The TCA cycle is a very efficient way to convert the acetyl-CoA pool into biomass and energy, and it results in the evolution of two CO2 molecules. Growth on acetate, fatty acids, or aromatics requires the activation of the glyoxylate shunt and gluconeogenesis pathways. By converting isocitrate to malate and bypassing half the TCA cycle, these two carbons are retained at the expense of energy production (Fig. 1). During fast growth in glucose or tryptone-based medium, E. coli and several other organisms excrete acetate to regenerate NAD + and to recycle coenzyme A. The acetate acidifies the medium and can repress the production of both native and heterologous proteins. Upon depletion of other carbon sources, the cells then retool their metabolism to reactivate acetate to acetyl-CoA, the canonical “acetate switch.” Finally, the excess acetyl-CoA can be harnessed for commercial interest through native or engineered pathways to produce fatty acids, bioplastics, pharmaceuticals, or biofuels.
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