Lecture on HMP Shunt (Hexose Monophosphate Shunt)

Introduction

• HMP Shunt Names: Hexose Monophosphate Shunt, Pentose Phosphate Pathway
• Function: Alternative pathway for the oxidation of glucose, parallel to glycolysis and TCA cycle.
• Products: CO2 and monophosphates

Pathway Overview

• Alternative pathway for glucose oxidation, generating CO2.
• Known as monophosphate due to generation of monophosphates (unlike bisphosphates in glycolysis).
• Also called Decanes and Herakar Pathway.
• Includes an important intermediate: phosphogluconate.

Steps in the HMP Shunt

Oxidative Phase

• Occurs in: Liver, adipose tissue, adrenal cortex, testes, ovaries, lactating mammary gland, erythrocytes.
• Main Sites: Liver, adipose tissue, and RBCs
• Initial Reaction: Glucose 6-phosphate → 6-phosphogluconolactone (rate-limiting step) via glucose 6-phosphate dehydrogenase.
  • Coenzyme: Requires NADP, converted to NADPH + H+.
• Subsequent Steps:
  • 6-phosphogluconolactone → 6-phosphogluconate via gluconolactone hydrolase.
  • 6-phosphogluconate → Ribulose 5-phosphate via 6-phosphogluconate dehydrogenase.
  • Generates NADPH, crucial for fatty acid, cholesterol, and steroid synthesis.

Non-Oxidative Phase

• Occurs in all cells: Synthesizes pentose sugars for DNA/RNA synthesis.
• Key Reactions:
  • Ribulose 5-phosphate → Xylulose 5-phosphate (epimerization).
  • Ribulose 5-phosphate → Ribose 5-phosphate (isomerization).
  • Transketolase reaction (thymine pyrophosphate-dependent).
  • Transaldolase reaction involving erythrose 4-phosphate and fructose 6-phosphate.
  • Regenerates glucose 6-phosphate.

Importance of HMP Shunt

• Products: NADPH and pentose sugars.
  • Pentose Sugars: DNA and RNA synthesis, nucleotide synthesis (e.g., ATP, FAD, NAD).
  • NADPH Uses:
    • Reductive biosynthesis of fatty acids, steroids, cholesterol.
    • Antioxidant functions, scavenging free radicals.
    • Maintenance of RBC membrane integrity.
    • Bactericidal action of macrophages.
    • Prevents formation of methemoglobin (keeps iron in ferrous state).
    • Maintains lens transparency.
    • Detoxification reactions (cytochrome P450 enzyme system).

Clinical Significance

Disorders Related to HMP Shunt

• G6PD Deficiency:
  • Symptomatic upon administration of oxidant drugs (e.g., primaquine, sulfa drugs).
  • Decreases NADPH production, affecting antioxidant functions.
  • Leads to hemolytic anemia or jaundice.
• Wernicke's Korsakoff Syndrome:
  • Related to transketolase activity in alcoholics.
  • Due to decreased thymine absorption and conversion.
  • Symptoms include global confusion, ophthalmoplegia, ataxia, memory loss, and psychosis.

Summary

• Divided into oxidative and non-oxidative phases.
• Occurs mainly in liver, adipose tissue, and RBCs.
• Generates NADPH and pentose sugars, vital for several biosynthetic pathways and cellular processes.