Figure 1.
Classical scheme of the interconversion between glucose and fatty acids in humans.
A While the conversion of glucose into fatty acids is possible, the product of β-oxidation of even-chain fatty acids, acetyl-CoA, can only enter the TCA cycle by reaction with oxaloacetate to citrate. However, in order to replenish the oxaloacetate consumed in this reaction, the TCA cycle has to be used resulting in the release of two carbon atoms in form of carbon dioxide. Hence, while two carbon atoms enter the TCA cycle in form of acetyl-CoA two others are lost and a net production of oxaloacetate which would be required for gluconeogenesis is not possible. B In some organisms the carbon releasing steps of the TCA cycle can be bypassed using the glyoxylate shunt (thick dotted reactions). In consequence, one mole of oxaloacetate can be produced from two mole of acetyl-CoA, allowing for gluconeogenesis from fatty acids. A list of abbreviations can be found in Table S1.
Figure 2.
Examples of elementary flux patterns.
A Schematic network of upper glycolysis and the pentose phosphate pathway with corresponding elementary flux patterns. Reactions of the subsystem are drawn in black. B–F Elementary flux patterns of the system. Thick black arrows correspond to the reactions of each flux pattern in the subsystem. Thick gray arrows indicate the reactions used by an elementary mode of the entire system using the reactions of the flux pattern in the subsystem. Individual flux ratios have been omitted for clarity. A list of abbreviations can be found in Table S1.
Figure 3.
Pathway for the conversion of fatty acids into glucose.
Essential reactions of the pathway are drawn with bold arrows. The presented pathway corresponds to the energetically most efficient pathway for the conversion of fatty acids into glucose (pathway 7 in Text S1). A similarly efficient pathway, pathway 14, uses almost the same route but converts acetol directly into methylglyoxal by reduction with NADPH. A list of abbreviations can be found in Table S1.
Figure 4.
Gluconeogenic pathways from fatty acids.
Only mitochondrial pathways for ketogenesis are shown since they represent the most important routes. Aqp9, Akr and one form of Acat2 are noted as irreversible in the model, but are lumped together with reversible reactions in the figure. A list of abbreviations can be found in Table S1. A complete list of pathways in ketogenesis and acetone metabolism is given in Text S1.
Figure 5.
Pathways for cytosolic NADPH production from mitochondrial NADH/NADPH.
The upper pathway depicts the transfer of electrons from mitochondrial NADH to cytosolic NADPH. The lower pathway depicts a transfer of electrons from mitochondrial NADPH to cytosolic NADPH. Please note that the second pathway involves the transport of oxoglutarate and citrate over the mitochondrial membrane and necessitates the antiport of L-malate and phosphoenolpyruvate, respectively. A list of enzymes can be found in Table S1.
Figure 6.
Pathway overview and storage efficiencies of selected compounds.
A Overview of ATP, NADPH and NADH consumption for gluconeogenesis from acetyl-CoA for all detected pathways (see Text S1). Furthermore, Gibbs free energy changes of all pathways for gluconeogenesis from acetyl-CoA and palmitate are given. B Gluconeogenic energy efficiencies and glucose storage efficiencies for selected compounds. Amino acids marked with an asterisk cannot be synthesized from glucose in humans. “Palmitic acid (eff.)” refers to the most energy efficient pathway for gluconeogenesis from fatty acids (pathway 7) and “Palmitic acid (ineff.)” to the most inefficient pathway (pathway 20).
Figure 7.
Gluconeogenic energy efficiency and glucose storage efficiency.
Figure 8.
Schematic representation of the iteration process for searching pathways.
Black arrows correspond to reactions belonging to the subsystems. A, D and F Subsystems used in the different iteration steps. B, C and E Selected elementary flux patterns (thick black arrows) and the reactions used by an associated elementary mode in the remaining system (thick gray arrows). If only one direction of a reversible reaction belongs to a subsystem, the reverse direction is omitted for clarity. G and H Elementary flux patterns of the final system producing R5P with the associated pathways through the entire system. A list of abbreviations can be found in Table S1.