Section 10: Hexose Monophosphate Shunt (HMP Shunt) / Pentose Phosphate Pathway

Key Functions of the HMP Shunt

1. Production of NADPH
   • Involved in synthesis of cholesterol, steroids, and fat.
   • Protects cells from oxidative stress.
   • Assists phagocytic cells by generating NADPH for the respiratory burst.
2. Production of Ribose 5-Phosphate
   • Used in nucleotide synthesis.

Pathway Overview

• Occurs exclusively in the cytoplasm.
• Important to distinguish enzymes present only in the cytoplasm versus those in both cytoplasm and mitochondria.

Detailed Pathway Steps

• Glucose 6-Phosphate Shunt: Diverts from glycolysis to produce Ribulose 5-Phosphate.
• Key Enzyme: Glucose 6-Phosphate Dehydrogenase (G6PD)
  • Produces NADPH.
  • Rate-limiting step of the HMP shunt.
• Conversion to Ribose 5-Phosphate
  • Ribulose 5-Phosphate is converted by an enzyme not highly emphasized.
• Trans-Ketolase
  • Converts Ribose 5-Phosphate to Fructose 6-Phosphate.
  • Requires Thiamine (Vitamin B1) as a cofactor.
  • Can be affected by thiamine deficiency.

Role of NADPH

1. Reductive Synthesis
   • Required for converting malonyl CoA to fatty acids.
   • G6PD deficiency can impair fat synthesis.
2. Protection from Oxidative Stress
   • Glutathione peroxidase neutralizes hydrogen peroxide in red blood cells.
   • G6PD deficiency reduces NADPH, affecting glutathione regeneration, increasing oxidative stress and leading to hemolysis.
   • Example: Bite cells are formed due to oxidative stress from fava beans in G6PD deficiency.
3. Support to Phagocytic Cells
   • Involved in respiratory burst; converts oxygen to superoxide anion using NADPH.
   • G6PD deficiency affects immune response by impairing respiratory burst.

Clinical Correlations

• G6PD Deficiency
  • Leads to decreased NADPH, affecting cell protection and immune system.
  • Hemolytic anemia can occur after oxidative stress (e.g., fava beans).
  • Ribose 5-Phosphate can still be synthesized due to reversible pathway converting Fructose 6-Phosphate to Ribose 5-Phosphate.

Practice Questions and Clinical Scenarios

• Understanding the mechanism for bite cell formation in G6PD deficiency.
• Exploring compensatory pathways enabling nucleotide synthesis despite G6PD deficiency.