Tricarboxylic Acid Cycle and Glyoxylate Bypass

Abstract

The tricarboxylic acid (TCA) cycle plays two essential roles in metabolism. First, under aerobic conditions the cycle is responsible for the total oxidation of acetyl-CoA that is derived mainly from the pyruvate produced by glycolysis. Second, TCA cycle intermediates are required in the biosynthesis of several amino acids. Although the TCA cycle has long been considered a "housekeeping" pathway in Escherichia coli and Salmonella enterica, the pathway is highly regulated at the transcriptional level. Much of this control is exerted in response to respiratory conditions. The TCA cycle gene-protein relationship and mutant phenotypes have been well studied, although a few loose ends remain. The realization that a "shadow" TCA cycle exists that proceeds through methylcitrate has cleared up prior ambiguities. The glyoxylate bypass has long been known to be essential for growth on carbon sources such as acetate or fatty acids because this pathway allowsnet conversion of acetyl-CoA to metabolic intermediates. Strains lacking this pathway fail to grow on these carbon sources, since acetate carbon entering the TCA cycle is quantitatively lost as CO2 resulting in the lack of a means to replenish the dicarboxylic acids consumed in amino acid biosynthesis. The TCA cycle gene-protein relationship and mutant phenotypes have been well studied, although the identity of the small molecule ligand that modulates transcriptional control of the glyoxylate cycle genes by binding to the IclR repressor remains unknown. The activity of the cycle is also exerted at the enzyme level by the reversible phosphorylation of the TCA cycle enzyme isocitrate dehydrogenase catalyzed by a specific kinase/phosphatase to allow isocitratelyase to compete for isocitrate and cleave this intermediate to glyoxylate and succinate.