Core Concepts
In this article, you will learn about an important metabolic pathway called Pentose Phosphate Pathway (PPP) and how it contributes to other metabolic processes in the cell like cholesterol synthesis and fatty acid synthesis.
Introduction
The pentose phosphate pathway (PPP) is a crucial metabolic pathway that diverges from glycolysis, functioning as a metabolic shunt to meet the specific needs of the cell for reducing power and biosynthetic precursors. This pathway is essential for producing NADPH for reductive biosynthesis and antioxidant defense, as well as ribose-5-phosphate for nucleic acid synthesis.
The PPP operates in the cytoplasm of cells and activates or deactivates based on cellular demands for NADPH, ribose-5-phosphate, and ATP. Activation typically occurs in response to high levels of NADP+, signaling a need for NADPH. Deactivation happens when NADPH levels are sufficient, inhibiting the key enzyme glucose-6-phosphate dehydrogenase (G6PDH), which you can see in the picture below. Additionally, glycolysis and other metabolic reactions can produce glucose-6-phosphate, the substrate for the PPP, linking the pathway to broader carbohydrate metabolism. The products of this shunt are important to cholesterol synthesis, fatty acid synthesis, and other processes within the cell.
Pentose Phosphate Pathway
The pathway can be divided into two distinct phases, the oxidative phase and the non-oxidative phase. The cycle starts with glucose-6-phosphate, an intermediate that occurs in glycolysis and diverts into the PPP. Recall that the first step in glycolysis is the phosphorylation of glucose to form glucose-6-phosphate. The hexokinase enzyme catalyzes this reaction, which traps glucose inside the cell and sets the stage for subsequent metabolic reactions.
The PPP can also utilize any molecules of glucose-6-phosphate produced by other methods like the breakdown of glycogen (glycogenolysis) or gluconeogenesis. This flexibility in sourcing glucose-6-phosphate allows the PPP to adapt to different metabolic conditions. For instance, during high energy demand, the PPP relies more on glycogenolysis or other sources as glycolysis focuses on ATP production. Conversely, when the cell has an energy surplus and low ATP demand, it reduces the need for alternative sources like gluconeogenesis and relies primarily on glycolysis for glucose-6-phosphate.
The picture above shows the first junction between glycolysis and the PPP, which begins with Glucose-6-phosphate.
Oxidative Phase (OXPPP)
This phase is called the oxidative phase because it involves oxidation-reduction reactions that produce NADPH. During these reactions, glucose-6-phosphate is oxidized, and NADP⁺ is reduced to NADPH. This NADPH produced can later be utilized in the synthesis of fatty acids. As mentioned, once glucose-6-phosphate is available, the enzyme G6PD catalyzes the oxidation of G6P to 6-phosphogluconolactone, producing NADPH as a reducing equivalent. Then, the enzyme 6PGL catalyzes the hydrolysis of 6-phosphogluconolactone to form 6-phosphogluconate. At this point, the enzyme 6PGD converts 6-phosphogluconate to ribulose-5-phosphate, producing NADPH and CO₂ in the process. The image below shows a schematic of the process.
Non-oxidative Phase (NonOXPPP)
The non-oxidative phase of the pentose phosphate pathway is a series of reversible reactions that interconvert various sugar phosphates. This phase allows the cell to produce ribose-5-phosphate for nucleotide synthesis or to recycle pentose phosphates back into glycolytic intermediates, depending on the cell’s needs. Unlike the oxidative phase, the non-oxidative phase does not involve redox reactions and does not produce NADPH.
This phase starts with a molecule from the previous phase, Ribulose-5-phosphate, which can be the substrate of an epimerase reaction to form xylulose-5-phosphate or an isomerase reaction to form ribose-5-phosphate.
The rest of the pathway includes a series of enzymes like transaldolases and transketolases, linking the pentose phosphate pathway with glycolysis and gluconeogenesis. In transaldolase reactions, 3 carbons transfer from a ketose to an aldose. Likewise, in transketolase reactions, 2 carbons are transferred.
In the figure below, we have colored the swapped carbons for clarity. From the previous step, we start with the ketose xylulose-5-phosphate and the aldose ribose-5-phosphate, which undergo a transketolase reaction, and the two carbons in the ketose (yellow carbons) are added to the aldose. This reaction yields two products; a 3-carbon sugar (glyceraldehyde-3-phosphate), and a 7-carbon sugar (Sedoheptulose-7-phosphate). These two undergo a transaldolase reaction where 3 carbons from the ketose (two yellow and green carbons) are transferred to the aldose, producing Erythrose-4-phosphate and Fructose-6-phosphate. The latter can directly enter glycolysis.
The PPP integrates with glycolysis when Xylulose-5-phosphate and Erythrose-4-phosphate produce Fructose-6-phosphate and Glyceraldehyde-3-phosphate via transketolase. These two sugars produced can directly enter glycolysis, as shown in the image at the beginning.
Maintaining Redox Balance within the Cell
As we saw before, the PPP synthesizes NADPH. This molecule is crucial in maintaining cytosol reduction by serving as a reducing agent in various biochemical processes. Most importantly, it regenerates reduced glutathione (GSH) from its oxidized form (GSSG), thereby supporting the cell’s primary antioxidant defense system. Glutathione reacts with reactive oxygen species (ROS), damaging the cell. It then converts into its oxidized form, glutathione disulfide. Glutathione reductase uses NADPH to reduce glutathione disulfide to GSH, maintaining cellular redox balance.