Lecture Notes: HMP Shunt (Hexose Monophosphate Shunt)

Introduction to HMP Shunt

• HMP Shunt Overview:
  • Also known as the Pentose Phosphate Pathway.
  • Alternative pathway for the oxidation of glucose, separate from glycolysis and TCA cycle.
  • Produces pentose sugars and NADPH.
  • Known as a shunt pathway, due to its role as an alternative oxidation route.
  • Involves monophosphates, unlike glycolysis which involves bisphosphates.
  • Also referred to as Decanes and Herakar pathway and Phosphogluconate oxidative pathway.

Key Phases of HMP Shunt

1. Oxidative Phase:

   • Occurs mainly in liver, adipose tissue, adrenal cortex, testes, ovaries, lactating mammary glands, and erythrocytes (RBCs).
   • Starts with glucose-6-phosphate.
   • Rate-limiting enzyme: Glucose 6-phosphate dehydrogenase.
   • Produces NADPH from NADP.
   • Involves conversion of glucose-6-phosphate to ribulose 5-phosphate.
   • Important for the generation of NADPH, which is used in fatty acid, cholesterol, and steroid synthesis.

2. Non-Oxidative Phase:

   • Occurs in all cells, involved in the synthesis of pentose sugars necessary for DNA and RNA synthesis.
   • Ribulose 5-phosphate is converted into ribose 5-phosphate (via isomerization) and xylulose 5-phosphate (via epimerization).
   • Transketolase and transaldolase reactions facilitate the formation of various intermediates like fructose 6-phosphate and glyceraldehyde 3-phosphate.
   • Transketolase reaction is TPP-dependent and important for evaluating thiamine status in the body.

Overall Reaction and Significance

• Utilization of glucose-6-phosphate results in the formation of NADPH and ribulose 5-phosphate.
• Oxidative phase results in the release of CO2.
• Liver and RBCs utilize a significant fraction of glucose through this pathway.

Importance of HMP Shunt Products

• NADPH Functions:

  • Reductive biosynthesis of fatty acids, steroids, and cholesterol.
  • Free radical scavenging and antioxidant functions.
  • Maintenance of RBC membrane integrity.
  • Supports bactericidal action of macrophages.
  • Prevents formation of methemoglobin.
  • Maintains transparency of lens.

• Pentose Sugars:

  • Precursor for nucleotide synthesis (e.g., ATP, FAD, NAD, CoA).
  • Essential for the synthesis of DNA and RNA.

Clinical Significance and Disorders

1. G6PD Deficiency:

   • Leads to decreased NADPH production.
   • Causes hemolytic anemia when exposed to oxidant drugs.
   • Drugs include primaquine, sulfamethoxazole, and acetanilide.

2. Wernicke's Korsakoff Syndrome:

   • Linked to decreased thiamine (vitamin B1) due to alcohol consumption.
   • Affects transketolase activity in HMP shunt.
   • Symptoms include confusion, ophthalmoplegia, ataxia, memory loss, and psychosis.

Summary

• HMP shunt is crucial for producing NADPH and pentose sugars.
• Operates through oxidative and non-oxidative phases primarily in certain tissues.
• Plays a critical role in biosynthesis processes, cellular protection mechanisms, and as a clinical diagnostic tool in specific enzyme deficiencies.