Pentose Phosphate Pathway

Hexose Monophosphate (HMP) Shunt

• About 10% of glucose per day enters this pathway, with the liver and RBCs metabolizing about 30% of glucose through this pathway.

Phases of HMP Shunt

Phase 1 (Oxidative Phase)

• Glucose-6-phosphate is oxidized, generating 2 molecules of NADPH, 1 molecule of pentose phosphate, and liberating 1 molecule of CO2.
• First reaction is catalyzed by Glucose-6-phosphate dehydrogenase (GPD), which is the rate-limiting step.

Phase 2 (Non-Oxidative Phase)

• Pentose phosphate is converted to intermediates of glycolysis.

Functions of NADPH+H

• Reductive biosynthesis (de novo synthesis of fatty acids and steroids).
• Maintenance of RBC membrane integrity:
  • Reduced glutathione (GSH) helps maintain the reduced state of SH groups in proteins, including hemoglobin and membrane proteins.
  • Oxidation of thiol groups in hemoglobin leads to denaturation of proteins and precipitation of insoluble mass inside RBCs (Heinz bodies).
  • Oxidation of membrane proteins makes RBCs rigid, leading to removal from circulation by macrophages.
• Reduction of glutathione:
  • NADPH+H reduces GS-SG into GSH, protecting thiol groups of cellular proteins from oxidation.
• Reduction of H2O2:
  • NADPH+H reduces H2O2, a reactive oxygen species (ROS) that can cause damage to DNA, proteins, unsaturated lipids, and cell membranes.

Deficiency of G6PD (Favism)

• Favism is a hemolytic anemia, especially after ingestion of fava beans and certain compounds, such as antibiotics, anti-malarial, and antipyretics, which increase oxidative stress.
• Deficiency of G6PD occurs in all cells, but is most severe in RBCs, where HMP-shunt is the only source of NADPH.
• Other cells have alternative NADPH sources, such as NADPH-dependent malate dehydrogenase and NADPH-dependent isocitrate dehydrogenase.
• Persons with G6PD deficiency show increased resistance to malarial infection.