Figure 1.

Carbon metabolism of mammalian cells in quiescent and activated states. In the quiescent state (thin blue arrows) a low amount of glucose, the major carbon source under these conditions, is taken up and oxidized mainly via the glycolytic pathway (1) and to a lesser extent by the (2). Pyruvate, the end product of glycolysis is transported to the mitochondria where it is further oxidized to CO₂ through the TCA (3). NADH, NADPH, and FADH₂, generated in (1), (2), and (3), respectively enter the electron transfer chain (ETC) where these electron donors are re-generated to NAD, NADP, and FAD thereby producing ATP by oxidative phosphorylation (OXPHOS) (5). ATP is also produced in the glycolytic pathway (1) by substrate phosphorylation. The anabolic pathways biosynthesizing the non-essential amino acids Ala, Ser, Asp, Asn, Glu, Gln, Pro as well as FAs, lipids, sterols, and nucleotides (green letters) are shut off or are running at a low level. In the activated state (red arrows), induced e.g., by growth factors, cytokines, activation of oncogenes, inactivation of tumor suppressors (see text for details), (1) and (2) are frequently highly induced, whereas (3) and (5) are now running at reduced levels. This metabolic condition is termed aerobic glycolysis or “Warburg effect.” In this state, pyruvate is converted to lactate thereby regenerating NAD which is needed for continuous glucose oxidation. Glutamine (Gln) and FAs may serve as alternative or additional carbon substrate(s) under these conditions. Gln is converted through glutaminolysis (4) to α-KG and FAs through ß-oxidation (6) to acetyl-CoA. Both metabolites can replenish the TCA. Under these conditions anabolic pathways are also activated as metabolites serving as precursors for the biosynthesis of amino acids, FAs/lipids/sterols, and nucleotides are produced in excess. (1): Glycolysis; (2): Pentose-phosphate pathway (PPP); (3): Tricarboxylic acid cycle (TCA); (4): Glutaminolysis; (5): Electron transfer chain/Oxidative phosphorylation (OXPHOS); (6): Fatty acid ß-oxidation (FAO). Ac-CoA, Acetyl-Coenzyme A; OAA, Oxaloacetate; Cit, Citrate; α-KG, α-ketoglutarate; Suc, Succinate; Fum, Fumarate; Mal, Malate. Blue box: Glucose transporters (GLUT-1-4), yellow box: glutamine transporter SLC1A5; ETC electron transfer chain, consisting of complexes I–IV and ATPase (complex V).