Central carbon metabolism in Mycobacterium tuberculosis: an unexpected frontier

Abstract

Recent advances in liquid chromatography and mass spectrometry have enabled the highly parallel, quantitative measurement of metabolites within a cell and the ability to trace their biochemical fates. In Mycobacterium tuberculosis (Mtb), these advances have highlighted major gaps in our understanding of central carbon metabolism (CCM) that have prompted fresh interpretations of the composition and structure of its metabolic pathways and the phenotypes of Mtb strains in which CCM genes have been deleted. High-throughput screens have demonstrated that small chemical compounds can selectively inhibit some enzymes of Mtb's CCM while sparing homologs in the host. Mtb's CCM has thus emerged as a frontier for both fundamental and translational research.

Figure 1

Bioinformatic inventory of the CCM network in Mtb. Pathway schematic depicting a bioinformatic reconstruction and inventory of Mtb’s CCM pathways. Abbreviations: CO₂, carbon dioxide; CoA, coenzyme A; GABA, gamma-aminobutyrate.

Figure 2

Experimentally annotated view of the CCM network of Mtb. Solid blue arrows denote biochemically confirmed reactions using purified recombinant enzymes; solid black lines denote biochemically confirmed reactions using Mtb protein extracts; dotted gray arrows denote genetically or bioinformatically inferred reactions; yellow highlighting indicates metabolomically detected reactions. Asterisk denotes multiple reactions not shown. Dagger denotes inferred detection of oxaloacetate using aspartate as a surrogate reporter that is thought to exist in rapid equilibrium with oxaloacetate. Abbreviations: CO₂, carbon dioxide; CoA, coenzyme A.