Figure 1.

Schematic diagram linking central carbon metabolism (CCM) and lipid metabolism in Mycobacterium tuberculosis (Mtb). (A) Catabolism of cholesterol and fatty acids (dark blue and black arrows) produces a variety of substrates, including succinyl-coenzyme A (CoA), propionyl-CoA and acetyl-CoA, which are channeled into CCM. While acetyl-CoA enters the tricarboxylic acid cycle (TCA) cycle (gold arrows), succinyl-CoA and propionyl-CoA enter the methylmalonyl cycle (dark purple arrows) and methylcitrate cycle (green arrows), respectively. Dashed (- -) dark blue arrow indicates catabolism of odd-chain fatty acids while solid dark blue arrow indicates catabolism of even-chain fatty acids. Fatty acids further serve as building blocks for other lipids, including triglycerides, which are involved in dormancy, while methylmalonyl-CoA serves as precursors of more complex Mtb lipids, including sulfolipids, acylated trehalose (light purple arrows). (B) Mtb is able to adapt to varying conditions through the diversity of its central carbon metabolism pathways, including the pentose phosphate pathway (dark green arrow), and variations in the TCA cycle. When under favorable conditions, carbon will flow through the classic TCA cycle (gold arrows), favoring the biosynthesis of precursors and generation of adenosine triphosphate (ATP). During infection when the bacterium is exposed to various stress conditions, carbon intermediates can also go through the reductive branch of the TCA cycle (orange arrows) or glyoxylate shunt (red arrows) in Mtb. These pathways are important for the regeneration of metabolites such as succinate, which is essential for instance in adaptation to hypoxia. During growth, intermediates of the TCA cycle must be withdrawn for the biosynthesis of fatty acids, nucleotide bases and amino acids through gluconeogenesis. These intermediates are replenished to achieve steady levels for normal TCA function by anaplerosis. The anaplerotic node is the metabolic link between glycolysis, gluconeogenesis (dark red arrows) and the TCA cycle (gold arrows) and acts as a switch that directs the flow of carbon distribution within the CCM. An example of anaplerosis is during growth on fatty acids, when the glyoxylate shunt (red arrows) serves to replenish malate via isocitrate lyase and malate synthase. Glucose further serves as a precursor for trehalose (grey arrow), which is a building block of glycolipids. Abbreviations: SL-1 = sulfolipid-1; FA = fatty acid; TCA = tricarboxylic acid cycle, CoA = coenzyme A; CO₂ = carbon dioxide; DAT = diacyl trehalose; PAT = poly-acyl trehalose; PDIM = phthiocerol dimycocerosate; TMM = trehalose monomycolate; TDM = trehalose dimycolate. Note: the schematic is a simplified form and do not represent all steps of the biosynthesis and catabolic pathways of the various metabolites.