Biochemistry: HMP Shunt (Hexose Monophosphate Shunt)

Introduction

• HMP Shunt is also known as:
  • Pentose Phosphate Pathway
  • Hexose Monophosphate Pathway
  • Decanes & Horecar Pathway
  • Phosphogluconate Oxidative Pathway
• An alternative pathway for glucose oxidation, alongside glycolysis and TCA cycle.
• Main functions:
  • Generates pentose sugars for DNA/RNA synthesis.
  • Produces NADPH for reductive biosynthesis.

Phases of HMP Shunt

Oxidative Phase

• Occurs mainly in:
  • Liver
  • Adipose tissue
  • Adrenal cortex, testes, ovaries
  • Lactating mammary gland
  • Erythrocytes (RBCs)
• Involves the following key steps:
  1. Glucose 6-Phosphate converted to 6-Phosphogluconolactone by Glucose 6-Phosphate Dehydrogenase (rate-limiting enzyme).
     • Requires NADP+; produces NADPH and H+.
  2. Conversion to 6-Phosphogluconate via Gluconolactone Hydrolase.
  3. 6-Phosphogluconate to Ribulose 5-Phosphate through a NADP+ dependent reaction (involves 6-Phosphogluconate Dehydrogenase).
     • Produces NADPH and liberates CO2.
  • Important for generating NADPH utilized in:
    • Fatty acid synthesis
    • Cholesterol synthesis
    • Steroid synthesis

Non-Oxidative Phase

• Occurs in all cells of the body.
• Synthesizes pentose sugars for nucleotide (DNA/RNA) synthesis.
• Key Reactions:
  1. Ribulose 5-Phosphate epimerized to Xylulose 5-Phosphate or isomerized to Ribose 5-Phosphate.
  2. Transketolase Reaction:
     • TPP-dependent; transfers 2-C units.
     • Converts Xylulose 5-Phosphate and Ribose 5-Phosphate to Sedoheptulose 7-Phosphate and Glyceraldehyde 3-Phosphate.
  3. Transaldolase Reaction:
     • Transfers 3-C units.
     • Products include Erythrose 4-Phosphate and Fructose 6-Phosphate.
  4. Subsequent reactions regenerate glucose 6-phosphate and produce CO2.

Importance of HMP Shunt

• Products:
  1. NADPH
     • Used in reductive biosynthesis (e.g., fatty acids, steroids)
     • Free radical scavenging with enzymes like superoxide dismutase and glutathione reductase.
     • Maintains RBC membrane integrity, preventing hemolytic jaundice.
     • Inhibits methemoglobin formation to maintain iron in the ferrous state.
     • Important for detoxification reactions via cytochrome P450.
  2. Pentose Sugars
     • Precursors for nucleotide synthesis (e.g., ATP, FAD, NAD, Coenzyme A).

Clinical Significance

• G6PD Deficiency:

  • Asymptomatic but problematic with oxidant drugs (e.g., primaquine, sulfa drugs) leading to hemolytic anemia.
  • Reduced NADPH impairs antioxidant defenses.

• Wernicke's Korsakoff Syndrome:

  • Related to Transketolase activity.
  • Reduced thiamine leads to functional deficiency impacting the HMP shunt.
  • Symptoms include global confusion, ophthalmoplegia, ataxia, memory loss, and psychosis.

Summary

• HMP Shunt is crucial for generating NADPH and pentose sugars.
• Plays a significant role in biosynthesis, antioxidation, and maintaining cellular health.