Pentose Phosphate Pathway: Regulation

Overview

• Focus on the regulation of the pentose phosphate pathway (PPP).
• Conversion of glucose 6-phosphate (G6P) to 6-phosphoglucono-δ-lactone is catalyzed by glucose 6-phosphate dehydrogenase (G6PD).
• G6PD is highly regulated based on the body's demand for NADPH and ribose 5-phosphate.

Regulation of Glucose 6-Phosphate Dehydrogenase (G6PD)

• The choice between PPP and glycolysis is influenced by ATP and NADPH levels.
• Low NADPH levels (i.e. high NADP+/NADPH ratio) stimulate G6PD → promotes the PPP to produce NADPH.
• High NADPH levels inhibit G6PD → reduces the flow through PPP.

Four Scenarios of PPP Regulation

Scenario 1: Need Ribose 5-Phosphate Only

• Utilize the non-oxidative phase of PPP.
• Ribose 5-phosphate is needed for nucleotide synthesis (DNA, RNA, ATP, NAD, FAD, CoA).
• Glycolytic intermediates (e.g., fructose 6-phosphate) are used to generate ribose 5-phosphate through transketolase and transaldolase reactions.

Scenario 2: Need Both Ribose 5-Phosphate and NADPH

• Utilize the oxidative phase of PPP.
• Oxidative phase generates both NADPH and ribose 5-phosphate.
• Crucial for nucleotide synthesis and other anabolic processes requiring NADPH (e.g., fatty acid synthesis).

Scenario 3: Need NADPH Only

• Oxidative phase and gluconeogenesis are active.
• G6P → 6-phosphoglucono-δ-lactone → 6-phosphogluconate → ribulose 5-phosphate → ribose 5-phosphate.
• Ribose 5-phosphate is converted back to glycolytic intermediates (e.g., GA3P, F6P) and further processed through gluconeogenesis to regenerate glucose.
• Ensures continuous production of NADPH without accumulation of ribose 5-phosphate.

Scenario 4: Need NADPH and ATP

• Both oxidative phase and glycolysis are utilized.
• G6P → 6-phosphoglucono-δ-lactone → 6-phosphogluconate → ribulose 5-phosphate → ribose 5-phosphate.
• Ribose 5-phosphate is converted to glycolytic intermediates and proceeds through glycolysis to produce ATP.

Importance of NADPH and Ribose 5-Phosphate

• NADPH: Vital for lipid synthesis, cholesterol synthesis, neurotransmitter synthesis, and nucleotide synthesis. It also plays a role in detoxifying reactive oxygen species.
• Ribose 5-Phosphate: Necessary for DNA and RNA synthesis, as well as the synthesis of ATP, NAD+, FAD, and Coenzyme A.

Free Radical Control and NADPH

• NADPH maintains reduced glutathione (GSH), a critical antioxidant.
• Oxidative stress mechanism: Superoxide anion (O₂⁻) and hydrogen peroxide (H₂O₂) are harmful byproducts that can cause oxidative damage.
• Enzymes involved:
  • Superoxide dismutase (SOD): Converts superoxide anion to hydrogen peroxide.
  • Catalase and Glutathione peroxidase: Convert hydrogen peroxide to water.
  • Glutathione reductase: Regenerates reduced glutathione using NADPH.
• G6PD Deficiency: Can lead to hemolytic anemia due to ineffective handling of oxidative stress.

Conclusion

• The pentose phosphate pathway is crucial for cellular metabolism, especially in managing oxidative stress and providing necessary metabolites for biosynthetic pathways.
• Proper regulation ensures efficient response to cellular demands for NADPH and ribose 5-phosphate.